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1.  Mortality and years of life lost by colorectal cancer attributable to physical inactivity in Brazil (1990–2015): Findings from the Global Burden of Disease Study 
PLoS ONE  2018;13(2):e0190943.
The aims of this study were to estimate all-cause and cause-specific mortality and years of life lost, investigated by disability-adjusted life-years (DALYs), due to colorectal cancer attributable to physical inactivity in Brazil and in the states; to analyze the temporal trend of these estimates over 25 years (1990–2015) compared with global estimates and according to the socioeconomic status of states of Brazil.
Databases from the Global Burden of Disease Study (GBD) for Brazil, Brazilian states and global information were used. It was estimated the total number and the age-standardized rates of deaths and DALYs for colorectal cancer attributable to physical inactivity in the years 1990 and 2015. We used the Socioeconomic Development Index (SDI).
Physical inactivity was responsible for a substantial number of deaths (1990: 1,302; 2015: 119,351) and DALYs (1990: 31,121; 2015: 87,116) due to colorectal cancer in Brazil. From 1990 to 2015, the mortality and DALYs due to colorectal cancer attributable to physical inactivity increased in Brazil (0.6% and 0.6%, respectively) and decreased around the world (-0.8% and -1.1%, respectively). The Brazilian states with better socioeconomic indicators had higher rates of mortality and morbidity by colorectal cancer due to physical inactivity (p<0.01). Physical inactivity was responsible for deaths and DALYs due to colorectal cancer in Brazil.
Over 25 years, the Brazilian population showed more worrisome results than around the world. Actions to combat physical inactivity and greater cancer screening and treatment are urgent in the Brazilian states.
PMCID: PMC5794056  PMID: 29390002
2.  Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach 
PLoS ONE  2018;13(2):e0191228.
Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called “diagnostic odysseys”. Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country—are rare.
To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.
This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.
We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3–70). The mean time elapsed from symptom onset to WES was 11 years (range 3–42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.
WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.
PMCID: PMC5794057  PMID: 29389947
3.  Revisiting the phylogeography, demography and taxonomy of the frog genus Ptychadena in the Ethiopian highlands with the use of genome-wide SNP data 
PLoS ONE  2018;13(2):e0190440.
Understanding the diversification of biological lineages is central to evolutionary studies. To properly study the process of speciation, it is necessary to link micro-evolutionary studies with macro-evolutionary mechanisms. Micro-evolutionary studies require proper sampling across a taxon’s range to adequately infer genetic diversity. Here we use the grass frogs of the genus Ptychadena from the Ethiopian highlands as a model to study the process of lineage diversification in this unique biodiversity hotspot. We used thousands of genome-wide SNPs obtained from double digest restriction site associated DNA sequencing (ddRAD-seq) in populations of the Ptychadena neumanni species complex from the Ethiopian highlands in order to infer their phylogenetic relationships and genetic structure, as well as to study their demographic history. Our genome-wide phylogenetic study supports the existence of approximately 13 lineages clustered into 3 species groups. Our phylogenetic and phylogeographic reconstructions suggest that those endemic lineages diversified in allopatry, and subsequently specialized to different habitats and elevations. Demographic analyses point to a continuous decrease in the population size across the majority of lineages and populations during the Pleistocene, which is consistent with a continuous period of aridification that East Africa experienced since the Pliocene. We discuss the taxonomic implications of our analyses and, in particular, we warn against the recent practice to solely use Bayesian species delimitation methods when proposing taxonomic changes.
PMCID: PMC5794058  PMID: 29389966
4.  A novel optogenetically tunable frequency modulating oscillator 
PLoS ONE  2018;13(2):e0183242.
Synthetic biology has enabled the creation of biological reconfigurable circuits, which perform multiple functions monopolizing a single biological machine; Such a system can switch between different behaviours in response to environmental cues. Previous work has demonstrated switchable dynamical behaviour employing reconfigurable logic gate genetic networks. Here we describe a computational framework for reconfigurable circuits in E.coli using combinations of logic gates, and also propose the biological implementation. The proposed system is an oscillator that can exhibit tunability of frequency and amplitude of oscillations. Further, the frequency of operation can be changed optogenetically. Insilico analysis revealed that two-component light systems, in response to light within a frequency range, can be used for modulating the frequency of the oscillator or stopping the oscillations altogether. Computational modelling reveals that mixing two colonies of E.coli oscillating at different frequencies generates spatial beat patterns. Further, we show that these oscillations more robustly respond to input perturbations compared to the base oscillator, to which the proposed oscillator is a modification. Compared to the base oscillator, the proposed system shows faster synchronization in a colony of cells for a larger region of the parameter space. Additionally, the proposed oscillator also exhibits lesser synchronization error in the transient period after input perturbations. This provides a strong basis for the construction of synthetic reconfigurable circuits in bacteria and other organisms, which can be scaled up to perform functions in the field of time dependent drug delivery with tunable dosages, and sets the stage for further development of circuits with synchronized population level behaviour.
PMCID: PMC5794059  PMID: 29389936
5.  Genetic stability of foot-and-mouth disease virus during long-term infections in natural hosts 
PLoS ONE  2018;13(2):e0190977.
Foot-and-mouth disease (FMD) is a severe infection caused by a picornavirus that affects livestock and wildlife. Persistence in ruminants is a well-documented feature of Foot-and-mouth disease virus (FMDV) pathogenesis and a major concern for disease control. Persistently infected animals harbor virus for extended periods, providing a unique opportunity to study within-host virus evolution. This study investigated the genetic dynamics of FMDV during persistent infections of naturally infected Asian buffalo. Using next-generation sequencing (NGS) we obtained 21 near complete FMDV genome sequences from 12 sub-clinically infected buffalo over a period of one year. Four animals yielded only one virus isolate and one yielded two isolates of different serotype suggesting a serial infection. Seven persistently infected animals yielded more than one virus of the same serotype showing a long-term intra-host viral genetic divergence at the consensus level of less than 2.5%. Quasi-species analysis showed few nucleotide variants and non-synonymous substitutions of progeny virus despite intra-host persistence of up to 152 days. Phylogenetic analyses of serotype Asia-1 VP1 sequences clustered all viruses from persistent animals with Group VII viruses circulating in Pakistan in 2011, but distinct from those circulating on 2008–2009. Furthermore, signature amino acid (aa) substitutions were found in the antigenically relevant VP1 of persistent viruses compared with viruses from 2008–2009. Intra-host purifying selective pressure was observed, with few codons in structural proteins undergoing positive selection. However, FMD persistent viruses did not show a clear pattern of antigenic selection. Our findings provide insight into the evolutionary dynamics of FMDV populations within naturally occurring subclinical and persistent infections that may have implications to vaccination strategies in the region.
PMCID: PMC5794060  PMID: 29390015
6.  Comparing fixed sampling with minimizer sampling when using k-mer indexes to find maximal exact matches 
PLoS ONE  2018;13(2):e0189960.
Bioinformatics applications and pipelines increasingly use k-mer indexes to search for similar sequences. The major problem with k-mer indexes is that they require lots of memory. Sampling is often used to reduce index size and query time. Most applications use one of two major types of sampling: fixed sampling and minimizer sampling. It is well known that fixed sampling will produce a smaller index, typically by roughly a factor of two, whereas it is generally assumed that minimizer sampling will produce faster query times since query k-mers can also be sampled. However, no direct comparison of fixed and minimizer sampling has been performed to verify these assumptions. We systematically compare fixed and minimizer sampling using the human genome as our database. We use the resulting k-mer indexes for fixed sampling and minimizer sampling to find all maximal exact matches between our database, the human genome, and three separate query sets, the mouse genome, the chimp genome, and an NGS data set. We reach the following conclusions. First, using larger k-mers reduces query time for both fixed sampling and minimizer sampling at a cost of requiring more space. If we use the same k-mer size for both methods, fixed sampling requires typically half as much space whereas minimizer sampling processes queries only slightly faster. If we are allowed to use any k-mer size for each method, then we can choose a k-mer size such that fixed sampling both uses less space and processes queries faster than minimizer sampling. The reason is that although minimizer sampling is able to sample query k-mers, the number of shared k-mer occurrences that must be processed is much larger for minimizer sampling than fixed sampling. In conclusion, we argue that for any application where each shared k-mer occurrence must be processed, fixed sampling is the right sampling method.
PMCID: PMC5794061  PMID: 29389989
7.  Intimate partner violence (IPV): The validity of an IPV screening instrument utilized among pregnant women in Tanzania and Vietnam 
PLoS ONE  2018;13(2):e0190856.
Intimate partner violence (IPV) is a global problem that affects one-third of all women. The present study aims to develop and determine the validity of a screening instrument for the detection of IPV in pregnant women in Tanzania and Vietnam and to determine the minimum number of questions needed to identify IPV.
An IPV screening instrument based on eight questions was tested on 1,116 Tanzanian and 1,309 Vietnamese women who attended antenatal care before 24 gestational weeks. The women were re-interviewed during their 30th-34th gestational week where the World Health Organization (WHO) IPV questionnaire was used as the gold standard. In all, 255 combinations of eight different questions were first tested on the Tanzanian study population where sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. In the evaluation of the performance of the question combinations, different IPV types and the frequency of abusive acts were considered. The question combinations that performed best in Tanzania were subsequently evaluated in the Vietnamese study population.
In Tanzania, a combination of three selected questions including one question on emotional IPV, one on physical IPV and one on sexual IPV was found to be most effective in identifying women who are exposed to at least one type of IPV during pregnancy (sensitivity = .80; specificity = .74). The performance of the identified combination was slightly less effective in Vietnam (sensitivity = .74; specificity = .68). Focusing on different IPV types, the best performance was found for exposure to physical IPV in both Tanzania (sensitivity = .93; specificity = .70) and Vietnam (sensitivity = .96; specificity = .55). In both countries, the sensitivity increased with the frequency of abuse whereas the specificity decreased.
By asking pregnant women three simple questions we were able to identify women who were exposed to IPV during pregnancy in two different countries. The question combination performed best in assessing physical IPV where it identified 93% and 96% of Vietnamese and Tanzanian women, respectively, who were exposed to physical IPV.
PMCID: PMC5794062  PMID: 29389954
8.  Different transfer pathways of an organochlorine pesticide across marine tropical food webs assessed with stable isotope analysis 
PLoS ONE  2018;13(2):e0191335.
Chlordecone is a persistent organochlorine pesticide used in the banana fields of the French West Indies from 1972 to 1993. Three marine habitats (mangroves, seagrass beds and coral reefs) of two study sites located downstream contaminated rivers were chosen to evaluate the level of contamination of marine food webs. On each habitat, the food chain collected included suspended organic matter, primary producers (macroalgae, algal turf, seagrass), zooplankton, symbiotic organisms (corals, sea anemones), primary consumers (herbivores, suspension feeders, biofilm feeders), omnivores and detritivores (lobsters, fish), secondary consumers (carnivores 1: invertebrate feeders, planktivores) and tertiary consumers (carnivores 2: invertebrate and fish feeders, piscivores). Log-linear regressions of the concentrations of chlordecone versus nitrogen isotopic ratios (δ15N) were used to assess the bioaccumulation of chlordecone along trophic food webs. At each site, bioconcentration and bioamplification take part on the transfer of chlordecone in marine organisms. In mangroves (i.e. close to the source of pollution), lower trophic magnification factors (TMF) indicated that bioconcentration prevailed over bioamplification phenomenon. The opposite phenomenon appeared on coral reefs in which bioconcentration processes were less important and bioamplification pathway became dominant. Far from the source of pollution, molecules of chlordecone seemed to be transfered to organisms mostly via trophic interactions rather than water contact.
PMCID: PMC5794063  PMID: 29390017
9.  Molecular typing of Legionella pneumophila isolates from environmental water samples and clinical samples using a five-gene sequence typing and standard Sequence-Based Typing 
PLoS ONE  2018;13(2):e0190986.
Inadequate discriminatory power to distinguish between L. pneumophila isolates, especially those belonging to disease-related prevalent sequence types (STs) such as ST1, ST36 and ST47, is an issue of SBT scheme. In this study, we developed a multilocus sequence typing (MLST) scheme based on two non-virulence loci (trpA, cca) and three virulence loci (icmK, lspE, lssD), to genotype 110 L. pneumophila isolates from various natural and artificial water sources in Guangdong province of China, and compared with the SBT. The isolates were assigned to 33 STs of the SBT and 91 new sequence types (nSTs) of the MLST. The indices of discrimination (IODs) of SBT and MLST were 0.920 and 0.985, respectively. Maximum likelihood trees of the concatenated SBT and MLST sequences both showed distinct phylogenetic relationships between the isolates from the two environments. More intragenic recombinations were detected in nSTs than in STs, and they were both more abundant in natural water isolates. We found out the MLST had a high discriminatory ability for the disease-associated ST1 isolates: 22 ST1 isolates were assigned to 19 nSTs. Furthermore, we assayed the discrimination of the MLST for 29 reference strains (19 clinical and 10 environmental). The clinical strains were assigned to eight STs and ten nSTs. The MLST could also subtype the prevalent clinical ST36 or ST47 strains: eight ST36 strains were subtyped into three nSTs and two ST47 strains were subtyped into two nSTs. We found different distribution patterns of nSTs between the environmental and clinical ST36 isolates, and between the outbreak clinical ST36 isolates and the sporadic clinical ST36 isolates. These results together revealed the MLST scheme could be used as part of a typing scheme that increased discrimination when necessary.
PMCID: PMC5794064  PMID: 29389983
10.  Multiband multi-echo simultaneous ASL/BOLD for task-induced functional MRI 
PLoS ONE  2018;13(2):e0190427.
Typical simultaneous blood oxygenation-level dependent (BOLD) and arterial spin labeling (ASL) sequences acquire two echoes, one perfusion-sensitive and one BOLD-sensitive. However, for ASL, spatial resolution and brain coverage are limited due to the T1 decay of the labeled blood. This study applies a sequence combining a multiband acquisition with four echoes for simultaneous BOLD and pseudo-continuous ASL (pCASL) echo planar imaging (MBME ASL/BOLD) for block-design task-fMRI. A multiband acceleration of four was employed to increase brain coverage and reduce slice-timing effects on the ASL signal. Multi-echo independent component analysis (MEICA) was implemented to automatically denoise the BOLD signal by regressing non-BOLD components. This technique led to increased temporal signal-to-noise ratio (tSNR) and BOLD sensitivity. The MEICA technique was also modified to denoise the ASL signal by regressing artifact and BOLD signals from the first echo time-series. The MBME ASL/BOLD sequence was applied to a finger-tapping task functional MRI (fMRI) experiment. Signal characteristics and activation were evaluated using single echo BOLD, combined ME BOLD, combined ME BOLD after MEICA denoising, perfusion-weighted (PW), and perfusion-weighted after MEICA denoising time-series. The PW data was extracted using both surround subtraction and high-pass filtering followed by demodulation. In addition, the CBF/BOLD response ratio and CBF/BOLD coupling were analyzed. Results showed that the MEICA denoising procedure significantly improved the BOLD signal, leading to increased BOLD sensitivity, tSNR, and activation statistics compared to conventional single echo BOLD data. At the same time, the denoised PW data showed increased tSNR and activation statistics compared to the non-denoised PW data. CBF/BOLD coupling was also increased using the denoised ASL and BOLD data. Our preliminary data suggest that the MBME ASL/BOLD sequence can be employed to collect whole-brain task-fMRI with improved data quality for both BOLD and PW time series, thus improving the results of block-design task fMRI.
PMCID: PMC5794066  PMID: 29389985
11.  Spiral tracing on a touchscreen is influenced by age, hand, implement, and friction 
PLoS ONE  2018;13(2):e0191309.
Dexterity impairments are well documented in older adults, though it is unclear how these influence touchscreen manipulation. This study examined age-related differences while tracing on high- and low-friction touchscreens using the finger or stylus. 26 young and 24 older adults completed an Archimedes spiral tracing task on a touchscreen mounted on a force sensor. Root mean square error was calculated to quantify performance. Root mean square error increased by 29.9% for older vs. young adults using the fingertip, but was similar to young adults when using the stylus. Although other variables (e.g., touchscreen usage, sensation, and reaction time) differed between age groups, these variables were not related to increased error in older adults while using their fingertip. Root mean square error also increased on the low-friction surface for all subjects. These findings suggest that utilizing a stylus and increasing surface friction may improve touchscreen use in older adults.
PMCID: PMC5794070  PMID: 29389940
12.  Combining multi-modality data for searching biomarkers in schizophrenia 
PLoS ONE  2018;13(2):e0191202.
Identification of imaging biomarkers for schizophrenia is an important but still challenging problem. Even though considerable efforts have been made over the past decades, quantitative alterations between patients and healthy subjects have not yet provided a diagnostic measure with sufficient high sensitivity and specificity. One of the most important reasons is the lack of consistent findings, which is in part due to single-mode study, which only detects single dimensional information by each modality, and thus misses the most crucial differences between groups. Here, we hypothesize that multimodal integration of functional MRI (fMRI), structural MRI (sMRI), and diffusion tensor imaging (DTI) might yield more power for the diagnosis of schizophrenia. A novel multivariate data fusion method for combining these modalities is introduced without reducing the dimension or using the priors from 161 schizophrenia patients and 168 matched healthy controls. The multi-index feature for each ROI is constructed and summarized with Wilk's lambda by performing multivariate analysis of variance to calculate the significant difference between different groups. Our results show that, among these modalities, fMRI has the most significant featureby calculating the Jaccard similarity coefficient (0.7416) and Kappa index (0.4833). Furthermore, fusion of these modalities provides the most plentiful information and the highest predictive accuracy of 86.52%. This work indicates that multimodal integration can improve the ability of distinguishing differences between groups and might be assisting in further diagnosis of schizophrenia.
PMCID: PMC5794071  PMID: 29389986
13.  Has the free maternal health policy eliminated out of pocket payments for maternal health services? Views of women, health providers and insurance managers in Northern Ghana 
PLoS ONE  2018;13(2):e0184830.
The free maternal health policy was implemented in Ghana in 2008 under the National Health Insurance Scheme (NHIS). The policy sought to eliminate out of pocket (OOP) payments and enhance the utilisation of maternal health services. It is unclear whether the policy had altered OOP payments for services. The study explored views on costs and actual OOP payments during pregnancy. The source of funding for payments was also explored.
A convergent parallel mixed methods design, involving quantitative and qualitative data collection approaches. The study was set in the Kassena-Nankana municipality, a rural area in Ghana. Women (n = 406) who utilised services during pregnancy were surveyed. Also, 10 focus groups discussions (FGDs) were held with women who used services during pregnancy as well as 28 in-depth interviews (IDIs) with midwives/nurses (n = 25) and insurance managers/directors (n = 3). The survey was analysed using descriptive statistics, focussing on costs from the women’s perspective. Qualitative data were audio recorded, transcribed and translated verbatim into English where necessary. The transcripts were read and coded into themes and sub-themes.
The NHIS did not cover all expenses in relation to maternal health services. The overall mean for OOP cost during pregnancy was GH¢17.50 (US$8.60). Both FGDs and IDIs showed that women especially paid for drugs and ultrasound scan services. Sixty-five percent of the women used savings, whilst twenty-two percent sold assets to meet the OOP cost. Some women were unable to afford payments due to poverty and had to forgo treatment. Participants called for payments to be eliminated and for the NHIS to absorb the cost of emergency referrals. All participants admitted the benefits of the policy.
Women needed to make payments despite the policy. Measures should be put in place to eliminate payments to enable all women to receive services and promote universal health coverage.
PMCID: PMC5794072  PMID: 29389995
14.  Age- and gender-specific reference intervals of TSH and free T4 in an iodine-replete area: Data from Korean National Health and Nutrition Examination Survey IV (2013–2015) 
PLoS ONE  2018;13(2):e0190738.
Establishment of the reference interval of thyroid-stimulating hormone (TSH) is critical in the diagnosis of thyroid dysfunction and is affected by age, gender, iodine nutrition, and ethnicity. The aim of this study was to determine the reference intervals of TSH and free thyroxin (FT4) from a large, nationwide data of Korea where iodine intake is more than adequate.
We analyzed data from the Korea National Health and Nutrition Examination Survey VI that measured serum TSH, FT4, and thyroid peroxidase antibody from 7,061 individuals (urinary iodine measurement in 6,565). Age- and gender-specific reference intervals were established from 95% confidence limits from the 2.5 to 97.5 percentile of TSH (log-transformed) and FT4 in reference populations.
The geometric mean of TSH was 2.16 ± 0.01 mIU/L, with the lowest value found in the middle aged group (2.04 ± 0.02 mIU/L) and higher values noted in age groups of 10–19 and over 70 years (2.38 ± 0.02 and 2.32 ± 0.07 mIU/L, respectively). The association of TSH and age was U-shaped. The overall reference interval of TSH was 0.59–7.03 mIU/L. Mean FT4 was 1.25 ± 0.003 ng/dL (16.09 ± 0.039 pmol/L), and it showed a small but continuous decrease after 20 years of age (P < 0.001). There was a significant positive correlation between TSH and urine iodine concentration (r = 0.154, P < 0.001).
The reference interval of TSH in Korea, where iodine intake is above the requirement, was 0.59–7.03 mIU/L and showed U-shaped change with age, which was a similar pattern to iodine intake. The reference interval of FT4 was 0.92–1.60 ng/dL. The geometric mean and upper limit of TSH were higher than those of Western populations, reflecting the paramount importance of iodine intake on thyroid function.
PMCID: PMC5794073  PMID: 29390008
15.  Structural investigations on mechanism of lapatinib resistance caused by HER-2 mutants 
PLoS ONE  2018;13(2):e0190942.
HER-2 belongs to the human epidermal growth factor receptor (HER) family. Via different signal transduction pathways, HER-2 regulates normal cell proliferation, survival, and differentiation. Recently, it was reported that MCF10A, BT474, and MDA-MB-231 cells bearing the HER2 K753E mutation were resistant to lapatinib. Present study revealed that HER-2 mutant K753E showed some contrasting behaviour as compared to wild, L768S and V773L HER-2 in complex with lapatinib while similar to previously known lapatinib resistant L755S HER-2 mutant. Lapatinib showed stable but reverse orientation in binding site of K753E and the highest binding energy among studied HER2-lapatinib complexes but slightly lesser than L755S mutant. Results indicate that K753E has similar profile as L755S mutant for lapatinib. The interacting residues were also found different from other three studied forms as revealed by free energy decomposition and ligplot analysis.
PMCID: PMC5794075  PMID: 29389942
16.  The effect of histone deacetylase inhibitors on AHSP expression 
PLoS ONE  2018;13(2):e0189267.
Alpha-hemoglobin stabilizing protein (AHSP) is a molecular chaperone that can reduce the damage caused by excess free α-globin to erythroid cells in patients with impaired β-globin chain synthesis. We assessed the effect of sodium phenylbutyrate and sodium valproate, two histone deacetylase inhibitors (HDIs) that are being studied for the treatment of hemoglobinopathies, on the expression of AHSP, BCL11A (all isoforms), γ-globin genes (HBG1/2), and some related transcription factors including GATA1, NFE2, EKLF, KLF4, and STAT3. For this purpose, the K562 cell line was cultured for 2, 4, and 6 days in the presence and absence of sodium phenylbutyrate and sodium valproate. Relative real-time qRT-PCR analysis of mRNA levels was performed to determine the effects of the two compounds on gene expression. Expression of all target mRNAs increased significantly (p < 0.05), except for the expression of BCL11A, which was down-regulated (p < 0.05) in the cells treated with both compounds relative to the levels measured for untreated cells. The findings indicated that sodium valproate had a more considerable effect than sodium phenylbutyrate (p < 0.0005) on BCL11A repression and the up-regulation of other studied genes. γ-Globin and AHSP gene expression continuously increased during the culture period in the treated cells, with the highest gene expression observed for 1 mM sodium valproate after 6 days. Both compounds repressed the expression of BCL11A (-XL, -L, -S) and up-regulated GATA1, NFE2, EKLF, KLF4, STAT3, AHSP, and γ-globin genes expression. Moreover, sodium valproate showed a stronger effect on repressing BCL11A and escalating the expression of other target genes. The findings of this in vitro experiment could be considered in selecting drugs for clinical use in patients with β-hemoglobinopathies.
PMCID: PMC5794076  PMID: 29389946
17.  Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda 
PLoS ONE  2018;13(2):e0191922.
The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum parasites. Thus, the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) on the selection of P. falciparum multidrug resistance-1 (Pfmdr1) alleles in clinical settings.
P. falciparum positive samples were collected from children aged 12–59 months in a clinical trial in DR Congo and Uganda. Pfmdr1 single nucleotide polymorphisms (SNPs) analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP) assays.
The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05). Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms. Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11–1.05, p = 0.04) while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42–2.47, p = 1.0). Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms.
We found limited impact of (re-)treatment with AL or ASAQ on selection for Pfmdr1 variants and haplotypes associated with resistance to partner drugs. These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent P.falciparum infections. Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines.
PMCID: PMC5794077  PMID: 29390014
18.  Acute effects of different dynamic exercises on hamstring strain risk factors 
PLoS ONE  2018;13(2):e0191801.
The purpose of the study was to examine the acute effects of different dynamic exercise interventions on hamstring muscle performance. Thirty-six young men with poor hamstring flexibility were randomly assigned to three intervention groups: jogging combined with dynamic open kinetic chain stretching (DS), jogging combined with dynamic closed kinetic chain stretching (lunge with eccentric hamstring windmills, LEC), and jogging only (CON) groups. Hamstring flexibility, muscle stiffness (area under the curve, AUC), joint position sense (JPS), maximal eccentric strength (ECC), and angle of peak torque (APT) were recorded before and immediately after the exercise interventions. The results showed that the hamstring flexibility increased in DS (p < 0.001); muscle stiffness decreased in DS and was lower than jogging (p < 0.001). Moreover, ECC increased in LEC and was higher than jogging and DS (p < 0.001). APT was different among 3 groups (p < 0.001). Decreased accuracy of JPS was found in DS and jogging (p < 0.001). In conclusion, the dynamic closed kinetic chain stretching (LEC) as compared to open kinetic chain stretching (DS) or jogging group, may be an effective technique to enhance muscle performance during the pre-competition warm-up routine.
PMCID: PMC5794078  PMID: 29390001
19.  Quality in dementia care: A cross sectional study on the Bio-Psycho-Social competencies of health care professionals 
PLoS ONE  2018;13(2):e0191440.
Professionals in dementia-care ought to be able to work within a Bio-Psycho-Social model. The objectives were to examine whether dementia-care is delivered in a Bio-Psycho-Social way, to explore the influencing factors and to evaluate the factorial validity of the ‘Bio-Psycho-Social-Dementia-Care scale’.
Design and setting
413 healthcare-professionals completed the ‘Bio-Psycho-Social-Dementia-Care scale’. Differences between groups (settings, professions, years of experience) were calculated with a student’s t-test and one-way ANOVA. The facture structure of the scale was evaluated using a confirmatory factor analysis.
The factor-analysis confirmed the 5 subscale-structure (1) networking, (2) using the client’s expertise, (3) assessment and reporting, (4) professional knowledge and skills and (5) using the environment. (No significant differences were found between professionals in residential care and community care for the subscales ‘networking’ and ‘using the client’s expertise’. Professionals in residential care score higher than community care for ‘assessment and reporting’ (p<0,05) and ‘professional knowledge and skills’ (p<0,01) but lower for ‘using the environment’ (p<0,001). The juniors score higher for ‘professional knowledge’ compared to seniors (p<0,01) and the seniors score better for ‘professional experience’ (p<0,01). The Cure and Care disciplines and the Therapy disciplines had higher values in ‘assessment and reporting’ compared to the Social Support disciplines (p<0,001 and p<0.001). The Therapy disciplines scored higher in ‘using professional knowledge and skills’ compared to the Social Support group (p 0.021) and the Cure and Care disciplines (p<0,001). The Social Support disciplines scored higher in ‘using the environment’ compared to the Therapy disciplines (p<0.001) and the Cure and care disciplines (p<0.001).
The Bio-Psycho-Social-Dementia-scale is a valid tool and offers opportunities not only to rate, but also to improve Bio-Psycho-Social functioning in dementia-care: increase interdisciplinary collaboration, facilitate assessment, combine the strengths of the different professions and install a heterogeneous team with regard to age and experience.
PMCID: PMC5794079  PMID: 29389937
20.  Photocleavage-based affinity purification of biomarkers from serum: Application to multiplex allergy testing 
PLoS ONE  2018;13(2):e0191987.
Multiplex serological immunoassays, such as implemented on microarray or microsphere-based platforms, provide greater information content and higher throughput, while lowering the cost and blood volume required. These features are particularly attractive in pediatric food allergy testing to facilitate high throughput multi-allergen analysis from finger- or heel-stick collected blood. However, the miniaturization and microfluidics necessary for creating multiplex assays make them highly susceptible to the “matrix effect” caused by interference from non-target agents in serum and other biofluids. Such interference can result in lower sensitivity, specificity, reproducibility and quantitative accuracy. These problems have in large part prevented wide-spread implementation of multiplex immunoassays in clinical laboratories. We report the development of a novel method to eliminate the matrix effect by utilizing photocleavable capture antibodies to purify and concentrate blood-based biomarkers (a process termed PC-PURE) prior to detection in a multiplex immunoassay. To evaluate this approach, it was applied to blood-based allergy testing. Patient total IgE was purified and enriched using PC-PURE followed by multiplex microsphere-based detection of allergen-specific IgEs (termed the AllerBead assay). AllerBead was formatted to detect the eight most common pediatric food allergens: milk, soy, wheat, egg, peanuts, tree nuts, fin fish and shellfish, which account for >90% of all pediatric food allergies. 205 serum samples obtained from Boston Children’s Hospital were evaluated. When PC-PURE was employed with AllerBead, excellent agreement was obtained with the standard, non-multiplex, ImmunoCAP® assay (average sensitivity above published negative predictive cutoffs = 96% and average Pearson r = 0.90; average specificity = 97%). In contrast, poor ImmunoCAP®-correlation was observed when PC-PURE was not utilized (average sensitivity above published negative predictive cutoffs = 59% and average Pearson r = 0.61; average specificity = 97%). This approach should be adaptable to improve a wide range of multiplex immunoassays such as in cancer, infectious disease and autoimmune disease.
PMCID: PMC5794080  PMID: 29389948
21.  Skill (or lack thereof) of data-model fusion techniques to provide an early warning signal for an approaching tipping point 
PLoS ONE  2018;13(2):e0191768.
Many coupled human-natural systems have the potential to exhibit a highly nonlinear threshold response to external forcings resulting in fast transitions to undesirable states (such as eutrophication in a lake). Often, there are considerable uncertainties that make identifying the threshold challenging. Thus, rapid learning is critical for guiding management actions to avoid abrupt transitions. Here, we adopt the shallow lake problem as a test case to compare the performance of four common data assimilation schemes to predict an approaching transition. In order to demonstrate the complex interactions between management strategies and the ability of the data assimilation schemes to predict eutrophication, we also analyze our results across two different management strategies governing phosphorus emissions into the shallow lake. The compared data assimilation schemes are: ensemble Kalman filtering (EnKF), particle filtering (PF), pre-calibration (PC), and Markov Chain Monte Carlo (MCMC) estimation. While differing in their core assumptions, each data assimilation scheme is based on Bayes’ theorem and updates prior beliefs about a system based on new information. For large computational investments, EnKF, PF and MCMC show similar skill in capturing the observed phosphorus in the lake (measured as expected root mean squared prediction error). EnKF, followed by PF, displays the highest learning rates at low computational cost, thus providing a more reliable signal of an impending transition. MCMC approaches the true probability of eutrophication only after a strong signal of an impending transition emerges from the observations. Overall, we find that learning rates are greatest near regions of abrupt transitions, posing a challenge to early learning and preemptive management of systems with such abrupt transitions.
PMCID: PMC5794081  PMID: 29389938
22.  Comparative genomics reveals differences in mobile virulence genes of Escherichia coli O103 pathotypes of bovine fecal origin 
PLoS ONE  2018;13(2):e0191362.
Escherichia coli O103, harbored in the hindgut and shed in the feces of cattle, can be enterohemorrhagic (EHEC), enteropathogenic (EPEC), or putative non-pathotype. The genetic diversity particularly that of virulence gene profiles within O103 serogroup is likely to be broad, considering the wide range in severity of illness. However, virulence descriptions of the E. coli O103 strains isolated from cattle feces have been primarily limited to major genes, such as Shiga toxin and intimin genes. Less is known about the frequency at which other virulence genes exist or about genes associated with the mobile genetic elements of E. coli O103 pathotypes. Our objective was to utilize whole genome sequencing (WGS) to identify and compare major and putative virulence genes of EHEC O103 (positive for Shiga toxin gene, stx1, and intimin gene, eae; n = 43), EPEC O103 (negative for stx1 and positive for eae; n = 13) and putative non-pathotype O103 strains (negative for stx and eae; n = 13) isolated from cattle feces. Six strains of EHEC O103 from human clinical cases were also included. All bovine EHEC strains (43/43) and a majority of EPEC (12/13) and putative non-pathotype strains (12/13) were O103:H2 serotype. Both bovine and human EHEC strains had significantly larger average genome sizes (P < 0.0001) and were positive for a higher number of adherence and toxin-based virulence genes and genes on mobile elements (prophages, transposable elements, and plasmids) than EPEC or putative non-pathotype strains. The genome size of the three pathotypes positively correlated (R2 = 0.7) with the number of genes carried on mobile genetic elements. Bovine strains clustered phylogenetically by pathotypes, which differed in several key virulence genes. The diversity of E. coli O103 pathotypes shed in cattle feces is likely reflective of the acquisition or loss of virulence genes carried on mobile genetic elements.
PMCID: PMC5794082  PMID: 29389941
23.  A test for clinal variation in Artemisia californica and associated arthropod responses to nitrogen addition 
PLoS ONE  2018;13(2):e0191997.
The response of plant traits to global change is of fundamental importance to understanding anthropogenic impacts on natural systems. Nevertheless, little is known about plant genetic variation in such responses or the indirect effect of environmental change on higher trophic levels. In a three-year common garden experiment, we grew the shrub Artemisia californica from five populations sourced along a 700 km latitudinal gradient under ambient and nitrogen (N) addition (20 kg N ha-1) and measured plant traits and associated arthropods. N addition increased plant biomass to a similar extent among all populations. In contrast, N addition effects on most other plant traits varied among plant populations; N addition reduced specific leaf area and leaf percent N and increased carbon to nitrogen ratios in the two northern populations, but had the opposite or no effect on the three southern populations. N addition increased arthropod abundance to a similar extent among all populations in parallel with an increase in plant biomass, suggesting that N addition did not alter plant resistance to herbivores. N addition had no effect on arthropod diversity, richness, or evenness. In summary, genetic variation among A. californica populations mediated leaf-trait responses to N addition, but positive direct effects of N addition on plant biomass and indirect effects on arthropod abundance were consistent among all populations.
PMCID: PMC5794083  PMID: 29390030
24.  Comparison of retinal vascular geometry in obese and non-obese children 
PLoS ONE  2018;13(2):e0191434.
Childhood obesity is associated with adult cardiometabolic disease. We postulate that the underlying microvascular dysfunction begins in childhood. We thus aimed to compare retinal vascular parameters between obese and non-obese children.
This was a cross-sectional study involving 166 children aged 6 to 12 years old in Malaysia. Ocular examination, biometry, retinal photography, blood pressure and body mass index measurement were performed. Participants were divided into two groups; obese and non-obese. Retinal vascular parameters were measured using validated software.
Mean age was 9.58 years. Approximately 51.2% were obese. Obese children had significantly narrower retinal arteriolar caliber (F(1,159) = 6.862, p = 0.010), lower arteriovenous ratio (F(1,159) = 17.412, p < 0.001), higher venular fractal dimension (F(1,159) = 4.313, p = 0.039) and higher venular curvature tortuosity (F(1,158) = 5.166, p = 0.024) than non-obese children, after adjustment for age, gender, blood pressure and axial length.
Obese children have abnormal retinal vascular geometry. These findings suggest that childhood obesity is characterized by early microvascular abnormalities that precede development of overt disease. Further research is warranted to determine if these parameters represent viable biomarkers for risk stratification in obesity.
PMCID: PMC5794084  PMID: 29389952
25.  Genotype distribution and treatment response among incarcerated drug-dependent patients with chronic hepatitis C infection 
PLoS ONE  2018;13(2):e0191799.
The prevalence of hepatitis C virus (HCV) infection is disproportionately high among prisoners, especially among those who are drug-dependent. However, current screening and treatment recommendations are inconsistent for this population, and appropriate care is not reliably provided. To address these problems, the present study aimed to identify unique characteristics and clinical manifestations of incarcerated patients with HCV infection. We included incarcerated patients who received treatment with pegylated-interferon combined with ribavirin at Mackay Memorial Hospital in Taitung and were serving sentences at either the Taiyuan Skill Training Institute or the Yanwan Training Institute. HCV genotypes 1 (41.4%), 3 (25.9%), and 6 (24.1%) were the most prevalent in the incarcerated patients. During the study period, we analyzed treatment response among 58 incarcerated patients and compared obtained results with treatment response among 52 patients who were living in the community. Higher sustained virological response rate was observed among patients with incarceration and HCV genotype other than 1. The odds ratios (corresponding 95% confidence intervals) for incarceration and genotype 1 were 2.75 (1.06–7.11) and 0.37 (0.14–0.99), respectively. Better treatment compliance among incarcerated patients might partially explain these results. The results of this study suggest that treatment of prisoners with HCV infection is feasible and effective. More appropriate and timely methods are needed to prevent HCV transmission among injection drug users inside prisons.
PMCID: PMC5794085  PMID: 29389957

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