Ranking Medical Terms to Support Expansion of Lay Language Resources for Patient Comprehension of Electronic Health Record Notes: Adapted Distant Supervision Approach

BACKGROUND: Medical terms are a major obstacle for patients to comprehend their electronic health record (EHR) notes. Clinical natural language processing (NLP) systems that link EHR terms to lay terms or definitions allow patients to easily access helpful information when reading through their EHR notes, and have shown to improve patient EHR comprehension. However, high-quality lay language resources for EHR terms are very limited in the public domain. Because expanding and curating such a resource is a costly process, it is beneficial and even necessary to identify terms important for patient EHR comprehension first. OBJECTIVE: We aimed to develop an NLP system, called adapted distant supervision (ADS), to rank candidate terms mined from EHR corpora. We will give EHR terms ranked as high by ADS a higher priority for lay language annotation-that is, creating lay definitions for these terms. METHODS: Adapted distant supervision uses distant supervision from consumer health vocabulary and transfer learning to adapt itself to solve the problem of ranking EHR terms in the target domain. We investigated 2 state-of-the-art transfer learning algorithms (ie, feature space augmentation and supervised distant supervision) and designed 5 types of learning features, including distributed word representations learned from large EHR data for ADS. For evaluating ADS, we asked domain experts to annotate 6038 candidate terms as important or nonimportant for EHR comprehension. We then randomly divided these data into the target-domain training data (1000 examples) and the evaluation data (5038 examples). We compared ADS with 2 strong baselines, including standard supervised learning, on the evaluation data. RESULTS: The ADS system using feature space augmentation achieved the best average precision, 0.850, on the evaluation set when using 1000 target-domain training examples. The ADS system using supervised distant supervision achieved the best average precision, 0.819, on the evaluation set when using only 100 target-domain training examples. The 2 ADS systems both performed significantly better than the baseline systems (P \u3c .001 for all measures and all conditions). Using a rich set of learning features contributed to ADS\u27s performance substantially. CONCLUSIONS: ADS can effectively rank terms mined from EHRs. Transfer learning improved ADS\u27s performance even with a small number of target-domain training examples. EHR terms prioritized by ADS were used to expand a lay language resource that supports patient EHR comprehension. The top 10,000 EHR terms ranked by ADS are available upon request

Pretreatment of Woven Jute FRP Composite and Its Use in Strengthening of Reinforced Concrete Beams in Flexure

Environmental awareness motivates researchers worldwide to perform studies of natural fibre reinforced polymer composites, as they come with many advantages and are primarily sustainable. The present study aims at evaluating the mechanical characteristics of natural woven jute fibre reinforced polymer (FRP) composite subjected to three different pretreatments, alkali, benzyl chloride, and lastly heat treatment. It was concluded that heat treatment is one of the most suitable treatment methods for enhancing mechanical properties of jute FRP. Durability studies on Jute FRP pertaining to some common environmental conditions were also carried out such as effect of normal water and thermal aging on the tensile strength of jute FRP followed by fire flow test. The heat treated woven jute FRP composites were subsequently used for flexural strengthening of reinforced concrete beams in full and strip wrapping configurations. The study includes the effect of flexural strengthening provided by woven jute FRP, study of different failure modes, load deflection behavior, effect on the first crack load, and ultimate flexural strength of concrete beams strengthened using woven jute FRP subjected to bending loads. The study concludes that woven jute FRP is a suitable material which can be used for flexural upgradation of reinforced concrete beams

Crystal structure of binary and ternary complexes of serine hydroxymethyltransferase from Bacillus stearothermophilus

Serine hydroxymethyltransferase (SHMT), a member of the α-class of pyridoxal phosphate-dependent enzymes, catalyzes the reversible conversion of serine to glycine and tetrahydrofolate to 5,10-methylene tetrahydrofolate. We present here the crystal structures of the native enzyme and its complexes with serine, glycine, glycine, and 5-formyl tetrahydrofolate (FTHF) from Bacillus stearothermophilus. The first structure of the serine-bound form of SHMT allows identification of residues involved in serine binding and catalysis. The SHMT-serine complex does not show any significant conformational change compared with the native enzyme, contrary to that expected for a conversion from an "open" to "closed" form of the enzyme. However, the ternary complex with FTHF and glycine shows the reported conformational changes. In contrast to the Escherichia coli enzyme, this complex shows asymmetric binding of the FTHF to the two monomers within the dimer in a way similar to the murine SHMT. Comparison of the ternary complex with the native enzyme reveals the structural basis for the conformational change and asymmetric binding of FTHF. The four structures presented here correspond to the various reaction intermediates of the catalytic pathway and provide evidence for a direct displacement mechanism for the hydroxymethyl transfer rather than a retroaldol cleavage

New perspectives on oxidized genome damage and repair inhibition by pro-oxidant metals in neurological diseases

The primary cause (s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, eg, oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region (s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases.The primary cause (s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, eg, oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region (s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases

Interactive flow behaviour and heat transfer enhancement in a microchannel with cross flow synthetic jet

This paper examines the effectiveness in combining a pulsating fluid jet for thermal enhancement in microchannel heat sinks. The proposed arrangement utilises an oscillating diaphragm to induce a high-frequency periodic fluid jet with zero net mass output at the jet orifice hence, termed "synthetic jet". The pulsed jet interacts with the fluid flow through microchannel passages altering their flow characteristics. The present study develops a 2-dimensional finite volume numerical simulation based on unsteady Reynolds-averaged Navier-Stokes equations for examining the microchannel-synthetic jet flow interaction. For a range of parametric conditions, the behaviour of this periodic flow with its special features is identified and the associated convective heat transfer rates are predicted. The results indicate that the pulsating jet leads to outstanding thermal performance in microchannel flow increasing its heat dissipation rate by about 4.3 times compared to a microchannel without jet interaction within the tested parametric range. The degree of thermal enhancement is seen to grow continuously to reach a steady value in the absence of fluid compressibility. The proposed strategy has an intrinsic ability for outstanding thermal characteristics without causing pressure drop increases in microchannel fluid passages, which is identified as a unique feature of the technique.The study also examines and presents the effects of fluid compressibility on the heat removal capacity of this arrangement. The technique is envisaged to have application potential in miniature electronic devices where localised cooling is desired over a base heat dissipation load

TDP-43/FUS in motor neuron disease: complexity and challenges

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases

Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease

Impact of H1N1 on Socially Disadvantaged Populations: Systematic Review

The burden of H1N1 among socially disadvantaged populations is unclear. We aimed to synthesize hospitalization, severe illness, and mortality data associated with pandemic A/H1N1/2009 among socially disadvantaged populations.Studies were identified through searching MEDLINE, EMBASE, scanning reference lists, and contacting experts. Studies reporting hospitalization, severe illness, and mortality attributable to laboratory-confirmed 2009 H1N1 pandemic among socially disadvantaged populations (e.g., ethnic minorities, low-income or lower-middle-income economy countries [LIC/LMIC]) were included. Two independent reviewers conducted screening, data abstraction, and quality appraisal (Newcastle Ottawa Scale). Random effects meta-analysis was conducted using SAS and Review Manager.Sixty-two studies including 44,777 patients were included after screening 787 citations and 164 full-text articles. The prevalence of hospitalization for H1N1 ranged from 17-87% in high-income economy countries (HIC) and 11-45% in LIC/LMIC. Of those hospitalized, the prevalence of intensive care unit (ICU) admission and mortality was 6-76% and 1-25% in HIC; and 30% and 8-15%, in LIC/LMIC, respectively. There were significantly more hospitalizations among ethnic minorities versus non-ethnic minorities in two studies conducted in North America (1,313 patients, OR 2.26 [95% CI: 1.53-3.32]). There were no differences in ICU admissions (n = 8 studies, 15,352 patients, OR 0.84 [0.69-1.02]) or deaths (n = 6 studies, 14,757 patients, OR 0.85 [95% CI: 0.73-1.01]) among hospitalized patients in HIC. Sub-group analysis indicated that the meta-analysis results were not likely affected by confounding. Overall, the prevalence of hospitalization, severe illness, and mortality due to H1N1 was high for ethnic minorities in HIC and individuals from LIC/LMIC. However, our results suggest that there were little differences in the proportion of hospitalization, severe illness, and mortality between ethnic minorities and non-ethnic minorities living in HIC

Magnesium and zinc diffused growth and characterization of strontium L(+) tartrate pentahydrate crystals

Single crystals of intrinsic strontium L(+) tartrate (IST), Mg2+ doped strontium L(+) tartrate (MDST) and Zn2+ doped strontium L(+) tartrate (ZDST) are grown using gel diffusion reaction method. Optimum condition for crystal growth is established by varying gel density, gel pH, concentration and matrix of supernatant solutions. EDAX analysis is made to measure stoichiometric composition and cationic distribution of the grown crystals. Fourier transform infrared (FTIR) and Laser Raman spectral studies unveil various functional groups in the grown crystals. Thermo gravimetric analysis (TGA) reveal decomposition behavior of the crystals for the temperature range of 30-1000oC. IST, MDST and ZDST crystals inborn with chemical formulae SrC4H4O6.5H2O, Sr0.9987Mg0.0013C4H4O6.5H2O and Sr0.9929Zn0.0071C4H4O6.5H2O respectively