Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells.
Previous studies suggest that the presence of antigen-specific polyfunctional T cells is correlated with improved pathogen clearance, disease control, and clinical outcomes; however, the molecular mechanisms responsible for the generation, function, and survival of polyfunctional T cells remain unknown. The study of polyfunctional T cells has been, in part, limited by the need for intracellular cytokine staining (ICS), necessitating fixation and cell membrane permeabilization that leads to unacceptable degradation of RNA. Adopting elements from prior research efforts, we developed and optimized a modified protocol for the isolation of high-quality RNA (i.e., RIN > 7) from primary human T cells following aldehyde-fixation, detergent-based permeabilization, intracellular cytokines staining, and sorting. Additionally, this method also demonstrated utility preserving RNA when staining for transcription factors. This modified protocol utilizes an optimized combination of an RNase inhibitor and high-salt buffer that is cost-effective while maintaining the ability to identify and resolve cell populations for sorting. Overall, this protocol resulted in minimal loss of RNA integrity, quality, and quantity during cytoplasmic staining of cytokines and subsequent flourescence-activated cell sorting. Using this technique, we obtained the transcriptional profiles of functional subsets (i.e., non-functional, monofunctional, bifunctional, polyfunctional) of CMV-specific CD8+T cells. Our analyses demonstrated that these functional subsets are molecularly distinct, and that polyfunctional T cells are uniquely enriched for transcripts involved in viral response, inflammation, cell survival, proliferation, and metabolism when compared to monofunctional cells. Polyfunctional T cells demonstrate reduced activation-induced cell death and increased proliferation after antigen re-challenge. Further in silico analysis of transcriptional data suggested a critical role for STAT5 transcriptional activity in polyfunctional cell activation. Pharmacologic inhibition of STAT5 was associated with a significant reduction in polyfunctional cell cytokine expression and proliferation, demonstrating the requirement of STAT5 activity not only for proliferation and cell survival, but also cytokine expression. Finally, we confirmed this association between CMV-specific CD8+ polyfunctionality with STAT5 signaling also exists in immunosuppressed transplant recipients using single cell transcriptomics, indicating that results from this study may translate to this vulnerable patient population. Collectively, these results shed light on the mechanisms governing polyfunctional T cell function and survival and may ultimately inform multiple areas of immunology, including but not limited to the development of new vaccines, CAR-T cell therapies, and adoptive T cell transfer.


The Aboveground Vegetation Type and Underground Soil Property Mediate the Divergence of Soil Microbiomes and the Biological Interactions.
The composition of the soil microbiome is influenced by environmental (abiotic) variables and biological interactions (biotic factors). To determine whether the aboveground vegetation and soil physicochemical properties were the main determinant of beta-diversity and biological interaction of soil microbial community, we sampled soils from the temperate coniferous forest and grassland. Clustering of operational taxonomic units was conducted using 16S rRNA gene. We found that the microbial composition of the rhizospheres, in which root exudates influence the microbial environment, show lower alpha-diversity than that of nonroot soils. The nonsignificant rhizosphere effect suggested other undetermined factors or stochastic processes accounted for microbial diversity in the rhizosphere. More significant microbe-microbe interactions were observed in forest and rhizosphere soils relative to the grassland soils. The elevated number of positive correlations for relative abundances in forest soil implied beneficial associations being common among bacteria, in particular within the rhizosphere environment. The particular soil properties generated by root exudates also alter the physicochemical properties of soil such as K and pH value, and might in turn favor the adoption of teamwork-cooperation strategies for microbe-microbe interactions, represented as large clusters of positive associations among bacterial taxa. Specific biological interactions differentiated the microbiomes within forest soils. Thus, the environmental selection pressure of aboveground vegetation accounts for differences between soil microbiomes while biotic factors are responsible for fine-scale differences of the microbial community in forest soils.


Electrochemical study on the adsorption of carbon oxides and oxidation of their adsorption products on platinum group metals and alloys.
CO(2) reduction and CO adsorption on noble metals (Pt, Rh, Pd) and their alloys (Pt-Rh, Pd-Pt, Pd-Rh, Pd-Pt-Rh) prepared as thin rough deposits have been studied by chronoamperometry (CA), cyclic voltammetry (CV) and the electrochemical quartz crystal microbalance (EQCM). The influence of alloy surface composition on the values of surface coverage, eps (electron per site) and potential of the oxidation of CO(2) reduction and CO adsorption products is shown. The oxidation of the adsorbate on Pt-Rh alloys proceeds more easily (at lower potentials) than on pure metals. On the other hand, in the case of Pd-Pt and Pd-Rh alloys the adsorbate oxidation is more difficult and requires higher potentials than on Pt or Rh. The analysis of the EQCM signal is presented for the case of adsorption and oxidation of carbon oxide adsorption products on the electrodes studied. The comparison of adsorption parameters and the EQCM response obtained for platinum group metals and alloys leads to the conclusion that reduced CO(2) cannot be totally identified with adsorbed CO.


Minding the gap: a decomposition of emergency department use by Medicaid enrollees and the uninsured.
To examine differences in Emergency Department (ED) utilization between Medicaid enrollees and the uninsured. We use nationally representative data for adults age 19-64 from the 2004 Medical Expenditure Panel Survey. We calculate descriptive statistics highlighting differences in distributions of measurable characteristics and logit regressions describing differences in the coefficients of the characteristics between the 2 groups. Blinder-Oaxaca nonlinear decomposition methods are applied to quantify the effect that differences in measurable characteristics between the groups have on the differences in ED utilization, as well as examine the magnitude of the effect on utilization of differences in behavior between the groups. Twenty-seven percent of Medicaid enrollees had an ED visit, whereas 10% of those uninsured the entire year had an ED visit. Roughly half of the utilization gap can be explained by differences in measurable characteristics. Although predisposing factors such as demographic and socioeconomic characteristics explain little of the gap, the variables capturing health limitations reflecting need explain a more substantial amount of the gap. Specifically, the higher presence of chronic conditions reported by Medicaid enrollees accounts for 18 percentage points of the gap, and reporting fair or poor health status explains 10 percentage points of the disparity. Decomposition analysis results show that differences in measurable characteristics between the groups explain half of the disparity in visits. The remaining portion of the gap in ED utilization is driven by differences in unmeasured or unobserved characteristics between the groups such as care-seeking behavioral differences.


Postpancreatectomy hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) definition.
Postoperative hemorrhage is one of the most severe complications after pancreatic surgery. Due to the lack of an internationally accepted, universal definition of postpancreatectomy hemorrhage (PPH), the incidences reported in the literature vary considerably, even in reports from randomized controlled trials. Because of these variations in the definition of what constitutes a PPH, the incidences of its occurrence are not comparable. The International Study Group of Pancreatic Surgery (ISGPS) developed an objective, generally applicable definition of PPH based on a literature review and consensus clinical experience. Postpancreatectomy hemorrhage is defined by 3 parameters: onset, location, and severity. The onset is either early (< or =24 hours after the end of the index operation) or late (>24 hours). The location is either intraluminal or extraluminal. The severity of bleeding may be either mild or severe. Three different grades of PPH (grades A, B, and C) are defined according to the time of onset, site of bleeding, severity, and clinical impact. An objective, universally accepted definition and clinical grading of PPH is important for the appropriate management and use of interventions in PPH. Such a definition also would allow comparisons of results from future clinical trials. Such standardized definitions are necessary to compare, in a nonpartisan manner, the outcomes of studies and the evaluation of novel operative treatment modalities in pancreatic surgery.


Fluorescent and photochemical properties of a single zinc finger conjugated to a fluorescent DNA-binding probe.
A single zinc finger derived from the DNA-binding domain of the glucocorticoid receptor (GR) has been tethered to the intercalating fluorophore thiazole orange, and the DNA recognition characteristics of the conjugate have been examined. DNA sequence specificity for the peptide-dye conjugate, determined by steady-state fluorescence measurements and photoactivated DNA cleavage experiments, reproduce the binding features of response element recognition found in the native GR. The thiazole orange is able to intercalate and fluoresce when the conjugate binds, at concentrations where little fluorescence is observed from either the conjugate alone or the conjugate mixed with DNA lacking the zinc finger target sequence. The conjugate preferentially targets a 5'-TGTTCT-3' sequence (the native glucocorticoid receptor element) with a dissociation constant of about 25 nM. Lower binding affinities (up to 10-fold) are observed for single site variants of this sequence, and much lower affinity (40-50-fold) is observed for binding to the estrogen response element (which differs from the glucocorticoid receptor element at two positions) as well as to nonspecific DNA. Footprinting reactions show a 4-6 base pair region that is protected by the zinc finger moiety. Photocleavage assays reveal a several base pair region flanking the recognition sequence where the tethered thiazole orange moiety is able to intercalate and subsequently cleave DNA upon visible light exposure. Thiazole orange is also shown to oxidize the 5'-G of remote GG sequences, depending on the details of the intervening DNA sequence. Small synthetic protein-dye conjugates such as this one are potentially useful for a variety of purposes including sequence-specific probes that work under physiological conditions (without melting and hybridization of DNA), sequence-specific photocleavage agents, and self-assembling components in electron and energy transfer systems that utilize DNA as a scaffold and/or photochemical medium.


Salvage total laryngectomy for squamous cell carcinoma of the larynx and hypopharynx: Validated prognostic nomograms predicting oncological outcomes.
Salvage total laryngectomy (STL) is a preferred treatment for patients with residual, recurrent, and second primary squamous cell carcinoma of the larynx/hypopharynx after (chemo)radiation. To individually estimate postoperative oncological outcomes, we designed and validated prognostic nomograms. We used a dataset of 290 patients who underwent STL. Nomograms predicting 2- and 5-year OS, DFS, and DSS were developed, using variables which are identified pre- or postoperatively. The nomograms were externally validated on a dataset of 109 patients. The nomograms based on postoperative variables performed better than those based on preoperative variables (OS: C = 0.68 vs. 0.64; DFS: C = 0.70 vs. 0.64; DSS: C = 0.74 vs. 0.64). The nomogram predicting DSS based on postoperative variables performed best. The presented prognostic nomograms for predicting oncological outcomes in patients who undergo STL are tools which allow for a reliable prognostic assessment.


Codon usage optimization of HIV type 1 subtype C gag, pol, env, and nef genes: in vitro expression and immune responses in DNA-vaccinated mice.
Codon usage optimization of human immunodeficiency virus type 1 (HIV-1) structural genes has been shown to increase protein expression in vitro as well as in the context of DNA vaccines in vivo; however, all optimized genes reported thus far are derived from HIV-1 (group M) subtype B viruses. Here, we report the generation and biological characterization of codon usage-optimized gag, pol, env (gp160, gp140, gp120), and nef genes from a primary (nonrecombinant) HIV-1 subtype C isolate. After transfection into 293T cells, optimized subtype C genes expressed one to two orders of magnitude more protein (as determined by immunoblot densitometry) than the corresponding wild-type constructs. This effect was most pronounced for gp160, gp140, Gag, and Pol (>250-fold), but was also observed for gp120 and Nef (45- and 20-fold, respectively). Optimized gp160- and gp140-derived glycoproteins were processed, incorporated into virus particles, and mediated virus entry when expressed in trans to complement an env-minus HIV-1 provirus. Mice immunized with optimized gp140 DNA developed antibody as well as CD4+ and CD8+ T cell immune responses that were orders of magnitude greater than those of mice immunized with wild-type gp140 DNA. These data confirm and extend previous studies of codon usage optimization of HIV-1 genes to the most prevalent group M subtype. Our panel of matched optimized and wild-type subtype C genes should prove valuable for studies of protein expression and function, the generation of subtype-specific immunological reagents, and the production of DNA-based sub-unit vaccines directed against a broader spectrum of viruses.


Topographical disorientation in a patient who never developed navigational skills: the (re)habilitation treatment.
Although many cases of topographical disorientation are described in the literature, very few attempts have been made to rehabilitate this deficit, most likely because it is a multi-faceted syndrome in which different patients are affected by different topographical deficits. Therefore, it is not easy to develop a single rehabilitation programme to improve all types of topographical disorders. We describe the rehabilitation of a young woman with selective and pervasive topographical disorientation who never developed navigational skills due to a cerebral malformation bilaterally involving the retrorolandic regions. During treatment, the patient was trained to explore her surroundings carefully, to orient herself and then to move in the environment using a language-based strategy. At the end of the treatment, the patient was able to navigate in the environment by adopting several cognitive strategies useful for orientation. This result was maintained at the one-year follow-up, at which time the patient was also able to reach locations she had never been to alone. These results suggest that even patients who have never developed the ability to orient themselves in the environment can still achieve very good functional recovery if they are accurately assessed and submitted to a specific rehabilitation intervention.


Burden of Disease Attributed to Waterborne Transmission of Selected Enteric Pathogens, Australia, 2010.
AbstractUniversal access to safe drinking water is a global priority. To estimate the annual disease burden of campylobacteriosis, nontyphoidal salmonellosis, cryptosporidiosis, giardiasis, and norovirus attributable to waterborne transmission in Australia, we multiplied regional World Health Organization (WHO) estimates of the proportion of cases attributable to waterborne transmission by estimates of all-source disease burden for each study pathogen. Norovirus was attributed as causing the most waterborne disease cases (479,632; 95% uncertainty interval [UI]: 0-1,111,874) followed by giardiasis and campylobacteriosis. The estimated waterborne disability-adjusted life year (DALY) burden for campylobacteriosis (2,004; 95% UI: 0-5,831) was 7-fold greater than other study pathogens and exceeded the WHO guidelines for drinking water quality (1 × 10-6 DALY per person per year) by 90-fold. However, these estimates include disease transmitted via either drinking or recreational water exposure. More precise country-specific and drinking water-specific attribution estimates would better define the health burden from drinking water and inform changes to treatment requirements.


Negative interactions and feedback regulations are required for transient cellular response.
Signal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activation nature of downstream signaling molecules. The factors which we have investigated are loops (feed forward and feedback loops), cross-talk of signal transduction pathways, and the change in the concentration of the signaling molecules. Based on our results we conclude that among these factors feedback loop and the cross-talks which directly inhibit the target protein dominantly controls the transient cellular response.


Efficacy of bezlotoxumab to prevent recurrent Clostridioides difficile infection (CDI) in patients with multiple prior recurrent CDI.
Among 23 patients with multiply recurrent Clostridiodies difficile infection (mrCDI) who received bezlotoxumab at the end of antibiotic treatment a sustained clinical response of 91 % at 30 days and 78 % at 90 days was achieved. Bezlotoxumab administered at the end of antibiotic treatment was effective in patients with mrCDI.


HIV epidemic, prevention technologies, and the new generations: trends and opportunities for epidemic response.
The United Nations has underscored the possibility of ending the HIV epidemic as a public health problem. However, an increase in the incidence among adolescents and youth has indicated a greater distance between HIV responses and the specificities of the new generations, which can maintain the epidemic for an extended period. Regards this matter, it is debated that the provision of a range of preventive methods, even if highly effective, and a conservatism that has internalized stigma within government policies, hinder the proper and essential dialogue between current preventive policies and the needs of the new generations. These generations are marked by a social representation of AIDS as a mild disease, by new gender and sexuality performances, and by the search for a more critical role in affective and sexual encounters, which includes frequent use of dating apps and substances. The hierarchy of the delivery of prevention methods is presented as a proposal for a new policy, prioritizing pre-exposure prophylaxis (PrEP) and addressing the social determinants of the HIV epidemic, including strategies to mitigate stigma. The importance of the participation of adolescents and youth in constructing the policy and the need for an intersectoral response are also reinforced.


Inter-individual and intra-individual variation of the effects of pulsed RF EMF exposure on the human sleep EEG.
Pulse-modulated radiofrequency electromagnetic fields (RF EMF) can alter brain activity during sleep; increases of electroencephalographic (EEG) power in the sleep spindle (13.75-15.25 Hz) and delta-theta (1.25-9 Hz) frequency range have been reported. These field effects show striking inter-individual differences. However, it is still unknown whether individual subjects react in a similar way when repeatedly exposed. Thus, our study aimed to investigate inter-individual variation and intra-individual stability of field effects. To do so, we exposed 20 young male subjects twice for 30 min prior to sleep to the same amplitude modulated 900 MHz (2 Hz pulse, 20 Hz Gaussian low-pass filter and a ratio of peak-to-average of 4) RF EMF (spatial peak absorption of 2 W/kg averaged over 10 g) 2 weeks apart. The topographical analysis of EEG power during all-night non-rapid eye movement sleep revealed: (1) exposure-related increases in delta-theta frequency range in several fronto-central electrodes; and (2) no differences in spindle frequency range. We did not observe reproducible within-subject RF EMF effects on sleep spindle and delta-theta activity in the sleep EEG and it remains unclear whether a biological trait of how the subjects' brains react to RF EMF exists.


An Improved Multiplex Real-Time SYBR Green PCR Assay for Analysis of 24 Target Genes from 16 Bacterial Species in Fecal DNA Samples from Patients with Foodborne Illnesses.
Here, we developed a new version of our original screening system (Rapid Foodborne Bacterial Screening 24; RFBS24), which can simultaneously detect 24 genes of foodborne pathogens in fecal DNA samples. This new version (RFBS24 ver. 5) detected all known stx2 subtypes, enterotoxigenic Escherichia coli (STh genotype), and Vibrio parahaemolyticus (trh2), which were not detected by the original RFBS24 assay. The detection limits of RFBS24 ver. 5 were approximately 5.6 × 10(-2)-5.6 × 10(-5) (ng DNA)/reaction, significantly lower (10- to 100-fold) than those of the original RFBS24 for the 22 target genes analyzed here. We also tested the new assay on fecal DNA samples from patients infected with Salmonella, Campylobacter, or enterohemorrhagic E. coli. The number of bacterial target genes detected by RFBS24 ver. 5 was greater than that detected by RFBS24. RFBS24 ver. 5 combined with an Ultra Clean Fecal DNA Isolation Kit showed adequate performance (sensitivity and specificity 89% and 100%, respectively, for Salmonella spp. and 100% and 83%, respectively, for Campylobacter jejuni) in terms of rapid detection of a causative pathogen during foodborne-illness outbreaks. Thus, RFBS24 ver. 5 is more useful than the previous assay system for detection of foodborne pathogens and offers quick simultaneous analysis of many targets and thus facilitates rapid dissemination of information to public health officials.


Visual attention in adults with attention-deficit/hyperactivity disorder before and after stimulant treatment.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder which frequently persists into adulthood. The primary goal of the current study was to (a) investigate attentional functions of stimulant medication-naïve adults with ADHD, and (b) investigate the effects of 6 weeks of methylphenidate treatment on these functions. The study was a prospective, non-randomized, non-blinded, 6-week follow-up design with 42 stimulant medication-naïve adult patients with ADHD, and 42 age and parental education-matched healthy controls. Assessments included measures of visual attention, based on Bundesen's Theory of Visual Attention (TVA), which yields five precise measures of aspects of visual attention; general psychopathology; ADHD symptoms; dyslexia screening; and estimates of IQ. At baseline, significant differences were found between patients and controls on three attentional parameters: visual short-term memory capacity, threshold of conscious perception, and to a lesser extent visual processing speed. Secondary analyses revealed no significant correlations between TVA parameter estimates and severity of ADHD symptomatology. At follow-up, significant improvements were found specifically for visual processing speed; this improvement had a large effect size, and remained when controlling for re-test effects, IQ, and dyslexia screen performance. There were no significant correlations between changes in visual processing speed and changes in ADHD symptomatology. ADHD in adults may be associated with deficits in three distinct aspects of visual attention. Improvements after 6 weeks of medication are seen specifically in visual processing speed, which could represent an improvement in alertness. Clinical symptoms and visual attentional deficits may represent separate aspects of ADHD in adults.


Functional effects of differentially expressed microRNAs in A549 cells exposed to MWCNT-7 or crocidolite.
Multi-walled carbon nanotubes (MWCNT) are engineered nanomaterials widely used in industrial and biomedical applications. Yet, MWCNT inhalation may induce pulmonary adverse effects, and the MWCNT-7 (Mitsui-7) has been classified as possibly carcinogenic to humans. However, its molecular mechanisms of action are poorly understood and there are no biomarkers of exposure for occupational monitoring. Several pulmonary diseases, including lung cancer, have been associated with alterations in microRNA expression that are used as biomarkers of disease progression, and differentially-expressed microRNAs (DE miRNAs) can also allow understanding the molecular effects induced by a toxicant. In this study, we identify DE miRNAs in A549 alveolar epithelial cells following 24 h exposure to MWCNT-7 or crocidolite, as well as their enriched cellular functional pathways. These indicate that both materials change cell survival, differentiation and proliferative properties under the influence of AMPK, FoxO, TGF-β and Hippo pathways, and their metabolic activity and cell-to-cell communication. In addition, MWCNT-7 affects the actin cytoskeleton, ubiquitin mediated proteolysis, and ECM-receptor interactions; crocidolite the PI3K-Akt and mTOR pathways, endocytosis, and central carbon metabolism. Since deregulation of these pathways may be related to carcinogenesis, an interaction network of DE miRNAs and corresponding target cancer-related genes was constructed, highlighting the carcinogenic potential of Mitsui-7.


Collapse of optical binding under secondary irradiation.
When an optically trapped and bound micrometer-sized chain of particles is subjected to a suitably oriented secondary laser beam above a threshold level of intensity, the structure will collapse. The effect arises from modifications to the interparticle energy landscapes owing to the superposition of optically induced potentials. From the theory it also emerges that, for particles separated by near-field distances, optically induced assemblies may be continuously transformed between linear, spherical, and lamellar forms. The results show scope for the optical fabrication of moldable nanoscale structures.


ATR regulates a G2-phase cell-cycle checkpoint in Arabidopsis thaliana.
Ataxia telangiectasia-mutated and Rad3-related (ATR) plays a central role in cell-cycle regulation, transmitting DNA damage signals to downstream effectors of cell-cycle progression. In animals, ATR is an essential gene. Here, we find that Arabidopsis (Arabidopsis thaliana) atr-/- mutants were viable, fertile, and phenotypically wild-type in the absence of exogenous DNA damaging agents but exhibit altered expression of AtRNR1 (ribonucleotide reductase large subunit) and alteration of some damage-induced cell-cycle checkpoints. atr mutants were hypersensitive to hydroxyurea (HU), aphidicolin, and UV-B light but only mildly sensitive to gamma-radiation. G2 arrest was observed in response to gamma-irradiation in both wild-type and atr plants, albeit with slightly different kinetics, suggesting that ATR plays a secondary role in response to double-strand breaks. G2 arrest also was observed in wild-type plants in response to aphidicolin but was defective in atr mutants, resulting in compaction of nuclei and subsequent cell death. By contrast, HU-treated wild-type and atr plants arrested in G1 and showed no obvious signs of cell death. We propose that, in plants, HU invokes a novel checkpoint responsive to low levels of deoxynucleotide triphosphates. These results demonstrate the important role of cell-cycle checkpoints in the ability of plant cells to sense and cope with problems associated with DNA replication.


Cross-Sectional Study on the Association between Dietary Patterns and Sarcopenia in Elderly Patients with Chronic Kidney Disease Receiving Conservative Treatment.
Sarcopenia is a poor prognostic factor in patients with chronic kidney disease (CKD). Adequate dietary patterns are important for preventing sarcopenia; however, evidence regarding the underlying association between sarcopenia and diet is insufficient. Therefore, in this study, we aimed to investigate the association between sarcopenia and dietary patterns in CKD patients receiving conservative treatment. In this cross-sectional study, 441 patients with conservative CKD were examined using the Asian Working Group for Sarcopenia diagnostic criteria. CKD was defined as an eGFR of <60 mL/min/1.73 m2 present for >3 months. The participants were divided into sarcopenia and non-sarcopenia groups, and dietary patterns were compared between the two groups using the dietary variety score, a simple dietary survey method that investigates the weekly frequency of consumption of 10 food groups. Logistic regression analysis for CKD G3 showed that female sex (odds ratio (OR): 0.166, 95% confidence interval (CI): 0.086-0.320), increased body mass index (OR: 0.663, 95% CI: 0.590-0.745), and almost daily consumption of green/yellow vegetables (OR: 0.350, 95% CI: 0.176-0.695) were positively associated with non-sarcopenia. Although further prospective studies are required, the results suggest that low frequent consumption of vegetables is associated with sarcopenia in patients with CKD.


3-LbNets: Tri-Labeling Deep Convolutional Neural Network for the Automated Screening of Glaucoma, Glaucoma Suspect, and No Glaucoma in Fundus Images.
Early detection of glaucoma, a widespread visual disease, can prevent vision loss. Unfortunately, ophthalmologists are scarce and clinical diagnosis requires much time and cost. Therefore, we developed a screening Tri-Labeling deep convolutional neural network (3-LbNets) to identify no glaucoma, glaucoma suspect, and glaucoma cases in global fundus images. 3-LbNets extracts important features from 3 different labeling modals and puts them into an artificial neural network (ANN) to find the final result. The method was effective, with an AUC of 98.66% for no glaucoma, 97.54% for glaucoma suspect, and 97.19% for glaucoma when analysing 206 fundus images evaluated with unanimous agreement from 3 well-trained ophthalmologists (3/3). When analysing 178 difficult to interpret fundus images (with majority agreement (2/3)), this method had an AUC of 80.80% for no glaucoma, 69.52% for glaucoma suspect, and 82.74% for glaucoma cases.Clinical relevance-This establishes a robust global fundus image screening network based on the ensemble method that can optimize glaucoma screening to alleviate the toll on those with glaucoma and prevent glaucoma suspects from developing the disease.


Impact of the open and closed tracheal suctioning system on the incidence of mechanical ventilation associated pneumonia: literature review.
Pneumonia is the most common nosocominal infection in intensive care units and mechanical ventilation is a significant factor associated to its development. The objective of this study was to describe the impact of the open and closed tracheal suction systems on the incidence of ventilation-associated pneumonia. A search in the Pubmed database was performed to identify randomized controlled trials, published from 1990 to November 2008. Nine studies were included. Of the studies reviewed, seven did not disclose any significant advantages of using the closed system when compared to th e open, whereas two reported that use of the closed system increased colonization rates but not incidence of ventilation-associated pneumonia and one observed that use of the closed system did not increase colonization of the respiratory tract but reduced the spread of infection resulting in decreased sepsis rates. Only two studies found a reduction in the incidence of ventilation-associated pneumonia with use of the closed system, and one revealed a 3.5 times greater risk of developing this infection with the open system. Results suggest that the impact of the open and closed tracheal suction system is similar on development of ventilation-associated pneumonia, choice of the suction system should therefore be based on other parameters. While the closed system increases risk of colonization of the respiratory tract, but has the advantages of continuing mechanical ventilation and lessening hemodynamic impairment.


Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro.
The neocortex is the most common target of subdural electrotherapy and noninvasive brain stimulation modalities, including transcranial magnetic stimulation (TMS) and transcranial current simulation (TCS). Specific neuronal elements targeted by cortical stimulation are considered to underlie therapeutic effects, but the exact cell type(s) affected by these methods remains poorly understood. We determined whether neuronal morphology or cell type predicted responses to subthreshold and suprathreshold uniform electric fields. We characterized the effects of subthreshold and suprathreshold electrical stimulation on identified cortical neurons in vitro. Uniform electric fields were applied to rat motor cortex brain slices, while recording from interneurons and pyramidal cells across cortical layers, using a whole-cell patch clamp. Neuron morphology was reconstructed after intracellular dialysis of biocytin. Based solely on volume-weighted morphology, we developed a parsimonious model of neuronal soma polarization by subthreshold electric fields. We found that neuronal morphology correlated with somatic subthreshold polarization. Based on neuronal morphology, we predict layer V pyramidal neuronal soma to be individually the most sensitive to polarization by optimally oriented subthreshold fields. Suprathreshold electric field action potential threshold was shown to reflect both direct cell polarization and synaptic (network) activation. Layer V/VI neuron absolute electric field action potential thresholds were lower than layer II/III pyramidal neurons and interneurons. Compared with somatic current injection, electric fields promoted burst firing and modulated action potential firing times. We present experimental data indicating that cortical neuron morphology relative to electric fields and cortical cell type are factors in determining sensitivity to sub- and supra-threshold brain stimulation.


Proteoglycan involvement during development of lesional pulmonary edema.
We evaluated the effect of pancreatic elastase (7 IU i.v.) on pulmonary interstitial pressure (Pip) in in situ rabbit lungs by a micropuncture technique through the intact parietal pleura. Pip was -10.8 +/- 2.2 (SD) cmH2O in the control condition, increased to +5.1 +/- 1.7 cmH2O at approximately 60 min [condition referred to as mild edema (ME)], and subsequently decreased to -0.15 +/- 0.8 cmH2O, remaining steady from 80 up to 200 min with a marked increase in lung wet-to-dry weight ratio [condition referred to as severe edema (SE)], suggesting an increase in tissue compliance. We functionally correlated the measured Pip to structural modifications of proteoglycans, the major interfibrillar component of the extracellular matrix (ECM). The strength of the noncovalent bonds linking proteoglycans to other ECM components decreased with increasing severity of edema, as indicated by the increased extractability of proteoglycans with guanidine hydrochloride. Total proteoglycan recovery (expressed as microgram hexuronate/g dry tissue) increased from 436.8 +/- 14 in the control condition to 495.3 +/- 23 and 547.0 +/- 10 in ME and SE, respectively. Gel-filtration chromatography showed in ME a fragmentation of heparan sulfate proteoglycans, suggesting that elastase treatment first affected basement membrane integrity, whereas large chondroitin sulfate proteoglycans were degraded only in SE. Elastase caused a fragmentation only of the core protein of proteoglycans, the binding properties of which to collagens, fibronectin, and hyaluronic acid were markedly decreased, as indicated by a solid-phase binding assay. The sequential degradation of heparan sulfate and chondroitin sulfate proteoglycans may account for the initial increase in microvascular permeability, followed by a loss of the native architecture of the ECM, which may be responsible for the increase in tissue compliance.


Placement of atrial pacing leads during atrial fibrillation. Feasibility and subsequent lead performance.
To assess the feasibility of placing permanent atrial pacing leads during atrial fibrillation (AF) and whether such leads function satisfactorily. Prospective study of 17 consecutive patients in whom permanent atrial leads were positioned during an episode of paroxysmal AF. Fluoroscopic position ('figure of 8' or side-to-side movement and anterior position in RAO projection), lead impedance (> 300 but < 1000 ohms) and intracardiac electrogram (average peak to peak amplitude > 1 mV) were used to define an acceptable lead position. At 8 weeks post implant we measured: pulse duration pacing threshold at 5 V; lead impedance at 5 V and 0.5 ms; intracardiac electrogram (EGM) signal amplitude. At the end of the study we reviewed patients to establish whether AF had become permanent. In all patients, follow-up demonstrated satisfactory lead function. All leads had impedances between 300 and 1000 ohms. Pacing thresholds were all < 0.1 ms at 5 V. Mean atrial EGM amplitude seen in sinus rhythm was 3.3 mV (range 1.2-8.4); in patients where all follow-up was in AF in was 2.1 mV (range 1.5-2.5). Nine patients (53%) developed permanent AF. Placing atrial leads during AF is feasible using the technique described. However, some patients progress to chronic AF, eliminating the benefits of atrial pacing.


The differential proliferative ability of satellite cells in Lantang and Landrace pigs.
Here, for the first time, we evaluate the hypothesis that the proliferative abilities of satellite cells (SCs) isolated from Lantang (indigenous Chinese pigs) and Landrace pigs, which differ in muscle characteristics, are different. SCs were isolated from the longissimus dorsi muscle of neonatal Lantang and Landrace pigs. Proliferative ability was estimated by the count and proliferative activity of viable cells using a hemocytometer and MTT assay at different time points after seeding, respectively. Cell cycle information was detected by flow cytometry. Results showed that there was a greater (P<0.05) number of SCs in Lantang pigs compared with Landrace pigs after 72 h of culture. The percentage of cell population in S phase and G(2)/M phases in Lantang pigs were higher (P<0.05), while in G(0)/G(1) phase was lower (P<0.05) in comparison with the Landrace pigs. The mRNA abundances of MyoD, Myf5, myogenin and Pax7 in SCs from Lantang pigs were higher (P<0.05), while those of myostatin, Smad3 and genes in the mammalian target of rapamycin (mTOR) pathway (with the exception of 4EBP1) were lower (P<0.05) than the Landrace pigs. Protein levels of MyoD, myogenin, myostatin, S6K, phosphorylated mTOR and phosphorylated eIF4E were consistent with the corresponding mRNA abundance. Collectively, these findings suggested that SCs in the two breeds present different proliferative abilities, and the proliferative potential of SCs in Lantang pigs is higher than in Landrace pigs.


A 76 year old female diagnosed with cystic fibrosis.
The diagnosis of Cystic Fibrosis (CF) requires a high clinical suspicion in patients presenting at all ages. Early recognition permits referral to a specialist centre and may reduce the morbidity and mortality associated with CF. We report the case of the oldest patient in Ireland diagnosed with CF at 76 years of age and highlight the clinical features of her presentation.


Minimal residual disease.
Monitoring of residual disease in patients with malignant hematologic disorders has been recognized as an important diagnostic tool for assessment of the response to treatment and the individual risk of relapse. In a number of malignancies, employment of sensitive techniques permitting the identification of tumor cells within a 10(4)-fold or greater excess of normal cells revealed that the presence and persistence of residual disease at this level does not necessarily imply inevitable relapse. Several studies demonstrated that surveillance of persisting neoplastic cells by quantitative techniques can provide prognostically relevant information on the sensitivity of the malignant population to the treatment applied and the biologic behavior of the residual tumor cell clone during and after therapy. It has been shown in different types of leukemia that investigation of the level or the dynamics of residual disease by sensitive and quantitative approaches can provide a basis for clinical decision making.


The Fungal and Bacterial Rhizosphere Microbiome Associated With Grapevine Rootstock Genotypes in Mature and Young Vineyards.
The microbiota colonizing the rhizosphere and the endorhizosphere contribute to plant growth, productivity, carbon sequestration, and phytoremediation. Several studies suggested that different plants types and even genotypes of the same plant species harbor partially different microbiomes. Here, we characterize the rhizosphere bacterial and fungal microbiota across five grapevine rootstock genotypes cultivated in the same soil at two vineyards and sampling dates over 2 years by 16S rRNA gene and ITS high-throughput amplicon sequencing. In addition, we use quantitative PCR (qPCR) approach to measure the relative abundance and dynamic changes of fungal pathogens associated with black-foot disease. The objectives were to (1) unravel the effects of rootstock genotype on microbial communities in the rhizosphere of grapevine and (2) to compare the relative abundances of sequence reads and DNA amount of black-foot disease pathogens. Host genetic control of the microbiome was evident in the rhizosphere of the mature vineyard. Microbiome composition also shifted as year of sampling, and fungal diversity varied with sampling moments. Linear discriminant analysis identified specific bacterial (i.e., Bacillus) and fungal (i.e., Glomus) taxa associated with grapevine rootstocks. Host genotype did not predict any summary metrics of rhizosphere α- and β-diversity in the young vineyard. Regarding black-foot associated pathogens, a significant correlation between sequencing reads and qPCR was observed. In conclusion, grapevine rootstock genotypes in the mature vineyard were associated with different rhizosphere microbiomes. The latter could also have been affected by age of the vineyard, soil properties or field management practices. A more comprehensive study is needed to decipher the cause of the rootstock microbiome selection and the mechanisms by which grapevines are able to shape their associated microbial community. Understanding the vast diversity of bacteria and fungi in the rhizosphere and the interactions between microbiota and grapevine will facilitate the development of future strategies for grapevine protection.


Esophageal perforation: the importance of early diagnosis and primary repair.
Esophageal perforation is associated with high morbidity and mortality rates, particularly if not diagnosed and treated promptly. Despite the many advances in thoracic surgery, the management of patients with esophageal perforation remains controversial. We performed a retrospective clinical review of 36 patients, 15 women (41.7%) and 21 men (58.3%), treated at our hospital for esophageal perforation between 1989 and 2002. The mean age was 54.3 years (range 7-76 years). Iatrogenic causes were found in 63.9% of perforations, foreign body perforation in 16.7%, traumatic perforation in 13.9% and spontaneous rupture in 5.5%. Perforation occurred in the cervical esophagus in 12 cases, thoracic esophagus in 13 and abdominal esophagus in 11. Pain was the most common presenting symptom, occurring in 24 patients (66.7%). Dyspnea was noted in 14 patients (38.9%), fever in 12 (33.3%) and subcutaneous emphysema in 25 (69.4%). Management of esophageal perforation included primary closure in 19 (52.8%), resection in seven (19.4%) and non-surgical therapy in 10 (27.8%). The 30-day mortality was found to be 13.9%, and mean hospital stay was 24.4 days. In the surgically treated group the mortality rate was three of 26 patients (11.5%), and two of 10 patients (20%) in the conservatively managed group. Survival was significantly influenced by a delay of more than 24 h in the initiation of treatment. Primary closure within 24 h resulted in the most favorable outcome. Esophageal perforation is a life threatening condition, and any delay in diagnosis and therapy remains a major contributor to the attendant mortality.


Ocean acidificationf affects the bioenergetics of marine mussels as revealed by high-coverage quantitative metabolomics.
Ocean acidification has become a major ecological and environmental problem in the world, whereas the impact mechanism of ocean acidification in marine bivalves is not fully understood. Cellular energy allocation (CEA) approach and high-coverage metabolomic techniques were used to investigate the acidification effects on the energy metabolism of mussels. The thick shell mussels Mytilus coruscus were exposed to seawater pH 8.1 (control) and pH 7.7 (acidification) for 14 days and allowed to recover at pH 8.1 for 7 days. The levels of carbohydrates, lipids and proteins significantly decreased in the digestive glands of the mussels exposed to acidification. The 14-day acidification exposure increased the energy demands of mussels, resulting in increased electron transport system (ETS) activity and decreased cellular energy allocation (CEA). Significant carry-over effects were observed on all cellular energy parameters except the concentration of carbohydrates and cellular energy demand (Ec) after 7 days of recovery. Metabolomic analysis showed that acidification affected the phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and glycine, serine and threonine metabolism. Correlation analysis showed that mussel cell energy parameters (carbohydrates, lipids, proteins, CEA) were negatively/positively correlated with certain differentially abundant metabolites. Overall, the integrated biochemical and metabolomics analyses demonstrated the negative effects of acidification on energy metabolism at the cellular level and implicated the alteration of biosynthesis and metabolism of amino acids as a mechanism of metabolic perturbation caused by acidification in mussels.


Socioeconomic Factors Predict Successful Supervised Exercise Therapy Completion.
Supervised exercise therapy (SET) for patients with intermittent claudication (IC) can lower the risk of progression to chronic limb threatening ischemia and amputation, while preserving and restoring functional status. Despite supporting evidence, it remains underutilized and among those who initiate programs, attrition rates are extremely high. We hypothesize that socioeconomic factors may represent significant barriers to SET completion. Patients with IC referred to SET at a multi-hospital, single-institution healthcare system (2018 - 2022) from a prospectively maintained database were retrospectively analyzed. Our primary endpoint was SET program completion and graduation, defined as completion of 36 sessions. Our secondary endpoints were vascular intervention within one year of referral and change in ankle-brachial index (ABI). Baseline demographics were assessed using standard statistical methods. Predictors of SET graduation were analyzed using multivariable logistic regression generating adjusted odds ratios (aOR) with 95% confidence intervals (95%CI). Change in ABI was analyzed using t-test between subgroups. Reasons for attrition were tabulated. Patient Health Questionnaire-9 (PHQ-9), metabolic equivalent level, Vascular QOL, Duke Activity Status (DASI), and ABI were analyzed using paired t-tests across the entire cohort. Fifty-two patients met inclusion criteria: mean age 67.85 ± 10.69 years, 19 (36.54%) females, mean baseline ABI 0.77 ± 0.16. The co-pays for 100% of patients were fully covered by primary and secondary insurance plans. Twenty-one (40.38%) completed SET. On multivariable analysis, residence in a zip code with median household income < $47,000 (aOR = 0.10 [95% CI, 0.01 - 0.76]; P = .03) and higher BMI (aOR = 0.81 [95% CI, 0.67 - 0.99; P = .04) were significant barriers to SET graduation. There were no differences in ABI change or vascular intervention within one year between graduates and non-graduates. Non-graduates reported transportation challenges (25.00%), lack of motivation (20.83%), illness/functional limitation (20.83%) as primary reasons for SET attrition. Metabolic Equivalent Level (P = <.01) and DASI scores (P = .04) were significantly greater after participating in a SET program. Although SET participation improves lower extremity and functionality outcomes, only 40% of referred patients completed therapy in our cohort. Our findings suggest that both socioeconomic and functional factors influence the odds of completing SET programs, indicating a need for holistic pre-referral assessment to facilitate enhanced program accessibility for these populations.


Is There any Survival Benefit of Maintenance Chemotherapy Following Adjuvant Chemotherapy in Patients with Resected Pancreatic Cancer Patients with Post-Surgery Elevated CA 19-9?
Pancreatectomy offers only potential for cure but is only possible in a minority of patients. Even in those patients who receive adjuvant chemotherapy, majority of them succumb to death due to metastases. Radiation Therapy Oncology Group 9704 showed that post-surgery CA 19-9 levels are an important predictor of survival. European study group for pancreatic cancer-3 showed that completion of all 6 cycles of adjuvant chemotherapy was an independent prognostic factor. Any survival benefit of an intensified chemotherapy strategy has not been demonstrated in patients with persistently elevated CA 19-9 following surgery. The object of this study was to investigate any benefit of maintenance chemotherapy following adjuvant in these patients. Twenty patients with R0 surgery of pancreatic cancer who received adjuvant chemotherapy with post-surgery elevated CA 19-9 but no radiographic evidence of cancer was identified from 2005-2017. Either biopsy or positron emission tomography scan determined recurrence of cancer. Efficacy endpoints including overall survival and disease-free survival were assessed. Maintenance and additional chemotherapeutic agents included 5-FU, capecitabine, platinum agents, irinotecan and nab-paclitaxel. CA 19-9 normalized in 3 patients while 22 persisted to be elevated or had further increase in the marker. Two patients underwent metastatectomy. Median disease-free survival was 14.5m (9-18), OS 29m (19-96) and OS rates were 80%, 50% at 1 and 2 years respectively. We believe that the longer overall survival of our patients with elevated CA 19-9 post-surgery was due to maintenance and additional chemotherapy following planned 6-months of adjuvant therapy, close monitoring with monthly CA 19-9 and 3-monthly computed tomography scans. Our study also underlines importance of collecting pre-surgery CA 19-9 and complete staging including chest. Prospective study aiming to evaluate role of maintenance or intensified chemotherapy or targeted agents are indicated.


CONDUCT AND REPORTING OF MULTIVARIATE NETWORK META-ANALYSES: A SCOPING REVIEW.
Combining multivariate and network meta-analysis methods simultaneously in a multivariate network meta-analysis (MVNMA) provides the methodological framework to analyze the largest amount of evidence relevant to decision-makers (i.e. from indirect evidence and correlated outcomes). The objectives of this scoping review were to summarize the characteristics of MVNMAs published in the health sciences literature, and map the methodological guidance available for MVNMA. We searched MEDLINE, EMBASE, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to 28 August 2023, along with citations of included studies, for quantitative evidence syntheses that applied MVNMA and articles addressing MVNMA methods. Pairs of reviewers independently screened potentially eligible studies. Collected data included bibliographic, methodological and analytical characteristics of included studies. We reported results as total numbers, frequencies and percentages for categorical variables, and medians and interquartile ranges for continuous variables that were not normally distributed. After screening 1,075 titles and abstracts, and 112 full texts, we included 38 unique studies; of which, 10 were quantitative evidence syntheses that applied MVNMA and 28 were articles addressing MVNMA methods. Among the 10 MVNMAs, the first was published in 2013, four used studies identified from already published systematic reviews and eight addressed pharmacological interventions, which were the most common interventions. They evaluated interventions for metastatic melanoma, colorectal cancer, prostate cancer, oral hygiene, disruptive behaviour disorders, rheumatoid arthritis, narcolepsy, type 2 diabetes and overactive bladder syndrome. Five MVNMAs analyzed two outcomes simultaneously and four MVNMAs analyzed three outcomes simultaneously. Among the articles addressing MVNMA methods, the first was published in 2007 and the majority provided methodological frameworks for conducting MVNMAs (26/28, 93%). One study proposed criteria to standardize reporting of MVNMAs and two proposed items relevant to the quality assessment of MVNMAs. Study authors used data from 19 different illnesses to provide illustrative examples within their methodological guidance. The application of MVNMA in the health sciences literature is uncommon. Many methodological frameworks are published; however, standardization, and specific criteria to guide reporting and quality assessment are lacking. This overview of the current landscape may help inform future conduct of MVNMAs and research on MVNMA methods.


Systematic review estimating the burden of dementia in the WHO Southeast Asia Region using Bayesian and frequentist approaches.
Rapid increase in life expectancy in low- and middle-income countries including the World Health Organization's Southeast Asia Region (SEAR) has resulted in an increase in the global burden of dementia, which is expected to become a leading cause of morbidity. Accurate burden estimates are key for informing policy and planning. Given the paucity of data, estimates were developed using both a Bayesian methodology and as well as a traditional frequentist approach to gain better insights into methodological approaches for disease burden estimates. Seven databases were searched for studies published between 2010-2018 regarding dementia prevalence in SEAR, generating 8 relevant articles. A random-effects model (REM) and a Bayesian normal-normal hierarchical model (NNHM) were used to obtain the pooled prevalence estimate of dementia for people aged 60 and above in SEAR. The latter model was also developed to estimate age-specific dementia prevalence. Using UN population estimates for SEAR, total and age-specific projections of the burden of dementia in 2015, 2020 and 2030 were calculated. The prevalence of dementia in SEAR was found to be 3% (95% confidence interval (CI) = 2-6%) in those above age 60 based on REM, and 3.1% (95% credible interval = 1.5-5.0%) based on the NNHM. The estimated prevalence varies with age, increasing from 1.6% (95% credible interval = 0.8-2.5%) in people aged 60-69 to 12.4% (95% credible interval = 5.6-20%) in people above the age of 80. The risk of developing dementia increased exponentially with age. The number of people living with dementia in SEAR in 2015 was estimated at 5.51 million (95% credible interval = 2.66-8.82), with projections of 6.66 million (95% credible interval = 3.21-10.7) in 2020 and 9.6 million (95% credible interval = 4.62-15.36) in 2030. The burden of dementia in SEAR is substantial and will continue to increase rapidly by 2030. The lack of research focusing on dementia in SEAR points to a significant under-recognition of this disease. The projected rise in dementia cases in the future should prompt urgent governmental response to address this growing public health issue. We also argue that given the overall paucity of data for the region, the Bayesian approach offers a promising methodology for improved estimates of disease prevalence and burden and should continue to be explored.


Systematic review of the association between socioeconomic status and bladder cancer survival with hospital type, comorbidities, and treatment delay as mediators.
To review the current evidence on the relationship between three proposed mediators (comorbidities, hospital type, and treatment delays) for the relationship between socioeconomic status (SES) and bladder cancer survival. Six different searches using OVID (Medline and Embase) were carried out to collate information available between the proposed mediators with both SES and survival in bladder cancer. This systematic review was conducted according to a pre-defined protocol and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 49 studies were included in the review across the six searches (one appeared in two searches). There was a wealth of studies investigating the relationship between each of the proposed mediators with survival in bladder cancer patients. In general, a higher SES, lower comorbidities, and a larger hospital volume were all found to be associated with a decreased risk of death in bladder cancer patients. There was, however, a paucity of studies investigating the associations between these mediators and SES in bladder cancer patients. To gain a deeper understanding of the relationship between SES and survival identified in several observational studies, further investigations into the relationship between the proposed mediators and SES are warranted. Moreover, modifiable mediators, eg, treatment delay, highlight the importance of the standardization of clinical care across SES groups for all bladder cancer patients.


Decreased expression of type 1 fimbriae by a pst mutant of uropathogenic Escherichia coli reduces urinary tract infection.
The pstSCAB-phoU operon encodes the phosphate-specific transport system (Pst). Loss of Pst constitutively activates the Pho regulon and decreases bacterial virulence. However, specific mechanisms underlying decreased bacterial virulence through inactivation of Pst are poorly understood. In uropathogenic Escherichia coli (UPEC) strain CFT073, inactivation of pst decreased urinary tract colonization in CBA/J mice. The pst mutant was deficient in production of type 1 fimbriae and showed decreased expression of the fimA structural gene which correlated with differential expression of the fimB, fimE, ipuA, and ipbA genes, encoding recombinases, mediating inversion of the fim promoter. The role of fim downregulation in attenuation of the pst mutant was confirmed using a fim phase-locked-on derivative, which demonstrated a significant gain in virulence. In addition, the pst mutant was less able to invade human bladder epithelial cells. Since type 1 fimbriae contribute to UPEC virulence by promoting colonization and invasion of bladder cells, the reduced bladder colonization by the pst mutant is predominantly attributed to downregulation of these fimbriae. Elucidation of mechanisms mediating the control of type 1 fimbriae through activation of the Pho regulon in UPEC may open new avenues for therapeutics or prophylactics against urinary tract infections.


Virchow's node as a first manifestation of ovarian serous carcinoma: case report.
Ovarian carcinoma is a malignancy with a poor prognosis especially in patients with advanced disease. The majority of patients with ovarian serous carcinoma are diagnosed in advanced stages. Palpable extraabdominal lymphadenopathy at the time of presentation is distinctly uncommon. This case report addresses a patient with serous ovarian carcinoma presenting as left supraclavicular lymphadenopathy (Virchow's node) and no other symptoms. Not only thyroid or thoracic malignancies but also ovarian malignancies like serous ovarian carcinoma could present with a supraclavicular lymph node without any other symptoms.


Co-delivery of doxorubicin and oleanolic acid by triple-sensitive nanocomposite based on chitosan for effective promoting tumor apoptosis.
Nanocomposites as "stevedores" for co-delivery of multidrugs hold great promise in addressing the drawbacks of traditional cancer chemotherapy. In this work, our strategy presents a new avenue for the stepwise release of two co-delivered agents into the tumor cells. The hybrid nanocomposite consists of a pH-responsive chitosan (CS), a thermosensitive poly(N-vinylcaprolactam) (PNVCL) and a functionalized cell-penetrating peptide (H6R6). Doxorubicin (DOX) and oleanolic acid (OA) are loaded into the nanocomposite (H6R6-CS-g-PNVCL). The system displayed a suitable size (∼190 nm), a high DOX loading (13.2 %) and OA loading efficiency (7.3 %). The tumor microenvironment triggered the nanocomposite to be selectively retained in tumor cells, then releasing the drugs. Both in vitro and in vivo studies showed a significant enhancement in antitumor activity of the co-delivered system in comparison to mono-delivery. This approach which relies on redox, pH and temperature effects utilizing co-delivery nanosystems may be beneficial for future applications in cancer chemotherapy.


A near-infrared fluorophore for live-cell super-resolution microscopy of cellular proteins.
The ideal fluorescent probe for bioimaging is bright, absorbs at long wavelengths and can be implemented flexibly in living cells and in vivo. However, the design of synthetic fluorophores that combine all of these properties has proved to be extremely difficult. Here, we introduce a biocompatible near-infrared silicon-rhodamine probe that can be coupled specifically to proteins using different labelling techniques. Importantly, its high permeability and fluorogenic character permit the imaging of proteins in living cells and tissues, and its brightness and photostability make it ideally suited for live-cell super-resolution microscopy. The excellent spectroscopic properties of the probe combined with its ease of use in live-cell applications make it a powerful new tool for bioimaging.


Chloroquine resistance of Plasmodium falciparum in Brazil detected by a simple in vitro method.
The sensitivity of Plasmodium falciparum to antimalarial drugs is primarily determined by observing changes in the level of parasitaemia after administration of drugs to man. Performance of such a study and interpretation of its results may present certain difficulties, especially when conducted among persons living in malarious areas. The present study was conducted to evaluate the usefulness of a simple in vitro method for detecting chloroquine-resistant strains among infected residents of Mato Grosso, Brazil. The findings indicated the participants were infected with chloroquine-resistant P. falciparum. Subsequent administration of a standard regimen of chloroquine (25 mg/kg) to these subjects confirmed the findings observed in vitro by failing to cure 28 out of 30 infections. This in vitro technique seems to provide a useful method of determining the presence or prevalence of chloroquine-resistant strains in a given area.


Enabling High Throughput Kinetic Experimentation by Using Flow as a Differential Kinetic Technique.
Kinetic data is most commonly collected through the generation of time-series data under either batch or flow conditions. Existing methods to generate kinetic data in flow collect integral data (concentration over time) only. Here, we report a method for the rapid and direct collection of differential kinetic data (direct measurement of rate) in flow by performing a series of instantaneous rate measurements on sequential small-scale reactions. This technique decouples the time required to generate a full kinetic profile from the time required for a reaction to reach completion, enabling high throughput kinetic experimentation. In addition, comparison of kinetic profiles constructed at different residence times allows the robustness, or stability, of homogeneously catalysed reactions to be interrogated. This approach makes use of a segmented flow platform which was shown to quantitatively reproduce batch kinetic data. The proline mediated aldol reaction was chosen as a model reaction to perform a high throughput kinetic screen of 216 kinetic profiles in 90 hours, one every 25 minutes, which would have taken an estimated continuous 3500 hours in batch, an almost 40-fold increase in experimental throughput matched by a corresponding reduction in material consumption.


Geometrically centered region: a "wet" model of protein binding hot spots not excluding water molecules.
A protein interface can be as "wet" as a protein surface in terms of the number of immobilized water molecules. This important water information has not been explicitly taken by computational methods to model and identify protein binding hot spots, overlooking the water role in forming interface hydrogen bonds and in filing cavities. Hot spot residues are usually clustered at the core of the protein binding interfaces. However, traditional machine learning methods often identify the hot spot residues individually, breaking the cooperativity of the energetic contribution. Our idea in this work is to explore the role of immobilized water and meanwhile to capture two essential properties of hot spots: the compactness in contact and the far distance from bulk solvent. Our model is named geometrically centered region (GCR). The detection of GCRs is based on novel tripartite graphs, and atom burial levels which are a concept more intuitive than SASA. Applying to a data set containing 355 mutations, we achieved an F measure of 0.6414 when ΔΔG ≥ 1.0 kcal/mol was used to define hot spots. This performance is better than Robetta, a benchmark method in the field. We found that all but only one of the GCRs contain water to a certain degree, and most of the outstanding hot spot residues have water-mediated contacts. If the water is excluded, the burial level values are poorly related to the ΔΔG, and the model loses its performance remarkably. We also presented a definition for the O-ring of a GCR as the set of immediate neighbors of the residues in the GCR. Comparative analysis between the O-rings and GCRs reveals that the newly defined O-ring is indeed energetically less important than the GCR hot spot, confirming a long-standing hypothesis.


[Excision of Carbohydrate-Modified dNMP Analogues from DNA 3' end by Human Apurinic/Apyrimidinic Endonuclease 1 (APE1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1)].
We have studied the excision efficiency of human apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) on matched or mismatched bases located at the 3' end of DNA primers. We have used model DNA duplexes, which mimic DNA structures that occur during either replication (DNA with a 3' recessed end) or repair (DNA with a single-strand break). Both APE1 and TDP1 are more efficient in removing ribose-modified dNMP residues from mismatched pairs rather than canonical pairs. Thus, both of these enzymes may act as proofreading factors during the repair synthesis catalyzed by DNA polymerases including DNA polymerase β (Polβ). The design of new DNA polymerase inhibitors, which act as DNA or RNA chain terminators, is one of the main strategies in the development of antiviral agents. The excision efficacy of APE1 and TDP1 has also been studied for 3'-modified DNA duplexes that contain ddNMP or phosphorylated morpholino nucleosides (MorB) commonly used as terminators in the DNA synthesis. We have also investigated the insertion of ddNTP and morpholino nucleotides catalyzed by Polβ and human immunodeficiency virus reverse transcriptase. This experiment has pointed to MorCyt, cytosine-containing morpholino nucleoside, as a potential antiviral agent.


Prognostic factors of long-term functioning and productivity after traumatic brain injury: a systematic review of prospective cohort studies.
To systematically review prospective cohort studies that investigated prognostic factors associated with long-term activity limitations or participation restrictions and productivity after a traumatic brain injury. PubMed and Psychinfo were searched from 1995 to April 2005, and references were checked. Publications were selected if the study assessed prognostic factors for activity limitations or participation restrictions at least one year post injury; outcome was measured with another or additional measure besides the Glasgow Outcome Scale; the design was a prospective cohort study of adult traumatic brain injury patients; the article was a full-text article written in English, French, German or Dutch. Two reviewers independently assessed methodological quality. A study was considered as 'high quality' if it satisfied at least half of the maximum available quality score. Thirty-five articles reporting on 14 cohorts were included. Due to heterogeneity in prognostic factors and outcome measures, a best-evidence synthesis was performed. All cohorts were of high quality. Strong evidence for predicting disability was found for older age, pre-injury unemployment, pre-injury substance abuse, and more disability at rehabilitation discharge. Strong prognostic factors for being non-productive were pre-injury unemployment, longer post-traumatic amnesia, more disability at rehabilitation admission, and pre-injury substance abuse. Older age, pre-injury unemployment, pre-injury substance abuse and more disability at rehabilitation discharge are important predictors of long-term disability. Pre-injury unemployment, longer post-traumatic amnesia, more disability at rehabilitation admission and pre-injury substance abuse are important predictors of being non-productive.


Plasmodium falciparum histone acetyltransferase, a yeast GCN5 homologue involved in chromatin remodeling.
The yeast transcriptional coactivator GCN5 (yGCN5), a histone acetyltransferase (HAT), is part of large multimeric complexes that are required for chromatin remodeling and transcriptional activation. Like other eukaryotes, the malaria parasite DNA is organized into nucleosomes and the genome encodes components of chromatin-remodeling complexes. Here we show that GCN5 is conserved in Plasmodium species and that the most homologous regions are within the HAT domain and the bromodomain. The Plasmodium falciparum GCN5 homologue (PfGCN5) is spliced with three introns, encoding a protein of 1,464 residues. Mapping of the ends of the PfGCN5 transcript suggests that the mRNA is 5.2 to 5.4 kb, consistent with the result from Northern analysis. Using free core histones, we determined that recombinant PfGCN5 proteins have conserved HAT activity with a substrate preference for histone H3. Using substrate-specific antibodies, we determined that both Lys-8 and -14 of H3 were acetylated by the recombinant PfGCN5. In eukaryotes, GCN5 homologues interact with yeast ADA2 homologues and form large multiprotein HAT complexes. We have identified an ADA2 homologue in P. falciparum, PfADA2. Yeast two-hybrid and in vitro binding assays verified the interactions between PfGCN5 and PfADA2, suggesting that they may be associated with each other in vivo. The conserved function of the HAT domain in PfGCN5 was further illustrated with yeast complementation experiments, which showed that the PfGCN5 region corresponding to the full-length yGCN5 could partially complement the yGCN5 deletion mutation. Furthermore, a chimera comprising the PfGCN5 HAT domain fused to the remainder of yeast GCN5 (yGCN5) fully rescued the yGCN5 deletion mutant. These data demonstrate that PfGCN5 is an authentic GCN5 family member and may exist in chromatin-remodeling complexes to regulate gene expression in P. falciparum.


Expanding the UTAUT2 framework to determine the drivers of mobile shopping behaviour among older adults.
In the current severe aging of the population, the problem of "digital divide" of the elderly has become increasingly prominent, and the elderly market represents a vast demographic that is increasingly becoming an important customer segment for mobile shopping in the future. However, there is currently insufficient attention given to the research on mobile shopping behavior among older adults. This study tries to answer what are the driving factors of mobile phone shopping behavior among the elderly? The purpose of this study is to analyze the factors that drive the elderly's mobile phone shopping behavior, and to establish a mobile phone shopping acceptance model for the elderly to predict the factors of the elderly's behavioral intention of using smart phones. Based on the second edition of Unified Theory of Acceptance and Use of Technology theory (UTAUT 2), this study proposed a mobile phone shopping acceptance model for the elderly. The study collected valid data from 389 Chinese elderly people through questionnaires and analyzed them using structural equation models. The results showed that utilitarian, anxiety, trust, performance expectancy, effort expectancy, social influence, facilitating conditions and habit directly impact the older adults' intention to engage in mobile shopping. Additionally, facilitating conditions, habit and the older adults' intention to engage in mobile shopping act as driving factors for actual use behavior. This study further expands the UTAUT theoretical model, provides a theoretical basis for the research of mobile shopping behavior of the elderly, and enricues the application groups and fields of the UTAUT theoretical model. The results of this study provide inspiration for the development, design and marketing of age-appropriate mobile shopping products, and contribute to the realization and further adoption of age-appropriate mobile shopping, and also contribute to promoting the active aging of the elderly.


Virtual reality and the transformation of medical education.
Medical education is changing. Simulation is increasingly becoming a cornerstone of clinical training and, though effective, is resource intensive. With increasing pressures on budgets and standardisation, virtual reality (VR) is emerging as a new method of delivering simulation. VR offers benefits for learners and educators, delivering cost-effective, repeatable, standardised clinical training on demand. A large body of evidence supports VR simulation in all industries, including healthcare. Though VR is not a panacea, it is a powerful educational tool for defined learning objectives and implementation is growing worldwide. The future of VR lies in its ongoing integration into curricula and with technological developments that allow shared simulated clinical experiences. This will facilitate quality interprofessional education at scale, independent of geography, and transform how we deliver education to the clinicians of the future.


Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling.
Microbial products are sensed through Toll-like receptors (TLRs) and trigger a program of dendritic cell (DC) maturation that enables DCs to activate T cells. Although an accepted hallmark of this response is eventual down-regulation of DC endocytic capacity, we show that TLR ligands first acutely stimulate antigen macropinocytosis, leading to enhanced presentation on class I and class II major histocompatibility complex molecules. Simultaneously, actin-rich podosomes disappear, which suggests a coordinated redeployment of actin to fuel endocytosis. These reciprocal changes are transient and require p38 and extracellular signal-regulated kinase activation. Thus, the DC actin cytoskeleton can be rapidly mobilized in response to innate immune stimuli to enhance antigen capture and presentation.


Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates.
Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC-MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.


Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19.
Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8+ T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future.


The isolation of an o-diphenal oxidase from third-instar larvae of the blowfly Calliphora erythrocephala.
1. The isolation of an o-diphenol oxidase from an acetone-dried powder of late-third-instar larvae of Calliphora erythrocephala was investigated. An insoluble and micro-crystalline fraction containing the enzyme activity was obtained after fractionating extracts of the acetone-dried powder with (NH4)2SO4 and acetone. 2. This fraction can be solubilized in 0.1% sodium dodecyl sulphate without loss of activity. 3. Polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate shows that the o-diphenol oxidase is a minor component of the extracts from the acetone-dried powder. 4. The o-diphenol oxidase was purified by zonal centrifugation on a sucrose density gradient in the presence of sodium dodecyl sulphate. 5. The amino acid composition of the purified enzyme resembles that of some other o-diphenol oxidases. 6. The subunit composition of the o-diphenol oxidase is discussed.


Gaps in completion and timeliness of breast surgery and adjuvant therapy: a retrospective cohort of Haitian patients with nonmetastatic breast cancer.
There are limited data on breast surgery completion rates and prevalence of care-continuum delays in breast cancer treatment programs in low-income countries. This study analyzes treatment data in a retrospective cohort of 312 female patients with non-metastatic breast cancer in Haiti. Descriptive statistics were used to summarize patient characteristics; treatments received; and treatment delays of > 12 weeks. Multivariate logistic regressions were performed to identify factors associated with receiving surgery and with treatment delays. Exploratory multivariate survival analysis examined the association between surgery delays and disease-free survival (DFS). Of 312 patients, 249 (80%) completed breast surgery. The odds ratio (OR) for surgery completion for urban vs. rural dwellers was 2.15 (95% confidence interval [CI]: 1.19-3.88) and for those with locally advanced vs. early-stage disease was 0.34 (95%CI: 0.16-0.73). Among the 223 patients with evaluable surgery completion timelines, 96 (43%) experienced delays. Of the 221 patients eligible for adjuvant chemotherapy, 141 (64%) received adjuvant chemotherapy, 66 of whom (47%) experienced delays in chemotherapy initiation. Presentation in the later years of the cohort (2015-2016) was associated with lower rates of surgery completion (75% vs. 85%) and with delays in adjuvant chemotherapy initiation (OR [95%CI]: 3.25 [1.50-7.06]). Exploratory analysis revealed no association between surgical delays and DFS. While majority of patients obtained curative-intent surgery, nearly half experienced delays in surgery and adjuvant chemotherapy initiation. Although our study was not powered to identify an association between surgical delays and DFS, these delays may negatively impact long-term outcomes.


Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice.
Scavenger receptor class B type I (SR-BI) is expressed in macrophages, where it has been proposed to facilitate cholesterol efflux. However, direct evidence that the expression of macrophage SR-BI is protective against atherosclerosis is lacking. In this study, we examined the in vivo role of macrophage SR-BI in atherosclerotic lesion development in the apolipoprotein (apo) E-deficient mouse model. ApoE-deficient mice with (n=16) or without (n=15) expression of macrophage SR-BI were created by transplanting lethally irradiated apoE-deficient mice with bone marrow cells collected from SR-BI-/- apoE-/- mice or SR-BI+/+ apoE-/- mice. The recipient mice were fed a chow diet for 12 weeks after transplantation for analysis of atherosclerosis. Quantification of macrophage SR-BI mRNA by real-time reverse transcription-polymerase chain reaction indicated successful engraftment of donor bone marrow and inactivation of macrophage SR-BI in recipient mice reconstituted with SR-BI-/- apoE-/- bone marrow. There were no significant differences in plasma lipid levels, lipoprotein distributions, and HDL subpopulations between the 2 groups. Analysis of the proximal aorta demonstrated an 86% increase in mean atherosclerotic lesion area in SR-BI-/- apoE-/- --> apoE-/- mice compared with SR-BI+/+ apoE-/- --> apoE-/- mice (109.50+/-18.08 versus 58.75+/-9.58x10(3) microm2; mean+/-SEM, P=0.017). No difference in cholesterol efflux from SR-BI+/+ apoE-/- or SR-BI-/- apoE-/- macrophages to HDL or apoA-I discs was detected. Expression of macrophage SR-BI protects mice against atherosclerotic lesion development in apoE-deficient mice in vivo without influencing plasma lipids, HDL subpopulations, or cholesterol efflux. Thus, macrophage SR-BI plays an antiatherogenic role in vivo, providing a new therapeutic target for the design of strategies to prevent and treat atherosclerosis.


Binding of metal ions and water molecules to nucleic acid bases: the influence of water molecule coordination to a metal ion on water-nucleic acid base hydrogen bonds.
The interactions of nucleic acid bases with non-coordinated and coordinated water molecules were studied by analyzing data in the Protein Data Bank (PDB) and by quantum chemical calculations. The analysis of the data in the crystal structures from the PDB indicates that hydrogen bonds involving oxygen or nitrogen atoms of nucleic acid bases and water molecules are shorter when water is bonded to a metal ion. These results are in agreement with the quantum chemical calculations on geometries and interaction energies of hydrogen bonds; the calculations on model systems show that hydrogen bonds of nucleic acid bases with water bonded to a metal ion are stronger than hydrogen bonds with non-coordinated water. These calculated values are similar to the strength of hydrogen bonds between nucleic acid bases. The results presented in this paper may be relevant to understand the role of water molecules and metal ions in the process of replication and stabilization of nucleic acids and also to understand the possible toxicity of metal ion interactions with nucleic acids.


Effectiveness of a youth-led early childhood care and education programme in rural Pakistan: A cluster-randomised controlled trial.
The United Nation's Sustainable Development Goals encompass lifelong learning from birth to youth to adulthood (Goal 4) and economic opportunities for young people (Goal 8). The targets include improving access to quality early childhood care and education (ECCE) as well as learning and training opportunities for adolescents and youth. Cross-generational models for young children and youth may offer opportunities to address the interconnections between goals and targets for the next generation. We investigated whether an ECCE programme for young children (3.5-6.5 years) delivered by female youth (18-24 years) in rural Pakistan would be effective on children's school readiness. In partnership with the National Commission for Human Development in Pakistan, we implemented the 'Youth Leaders for Early Childhood Assuring Children are Prepared for School' (LEAPS) programme to train female youth to deliver ECCE. The effectiveness of the LEAPS programme on children's school readiness was evaluated in a cluster-randomised controlled trial. We randomly allocated five clusters (villages) to receive the intervention (n = 170 children) and five clusters to control (n = 170 children). Children's school readiness was assessed after nine months of intervention exposure using the International Development and Early Learning Assessment tool. Analyses was by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT02645162. At endline, the intervention group had significantly higher school readiness scores (n = 166, mean percentage score 59.4, 95% CI 52.7 to 66.2) compared with the control group (n = 168, mean percentage score 45.5, 95% CI 38.8 to 52.3). The effect size (Cohen's d) was 0.3. Trained female youth delivered an ECCE programme that was effective in benefitting young children's school readiness. The cross-generational model is a promising approach to support early child development; however, further evaluation of the model is needed to assess the specific benefits to youth including their skills and economic development.


The early-life exposome: Description and patterns in six European countries.
Characterization of the "exposome", the set of all environmental factors that one is exposed to from conception onwards, has been advocated to better understand the role of environmental factors on chronic diseases. Here, we aimed to describe the early-life exposome. Specifically, we focused on the correlations between multiple environmental exposures, their patterns and their variability across European regions and across time (pregnancy and childhood periods). We relied on the Human Early-Life Exposome (HELIX) project, in which 87 environmental exposures during pregnancy and 122 during the childhood period (grouped in 19 exposure groups) were assessed in 1301 pregnant mothers and their children at 6-11 years in 6 European birth cohorts. Some correlations between exposures in the same exposure group reached high values above 0.8. The median correlation within exposure groups was >0.3 for many exposure groups, reaching 0.69 for water disinfection by products in pregnancy and 0.67 for the meteorological group in childhood. Median correlations between different exposure groups rarely reached 0.3. Some correlations were driven by cohort-level associations (e.g. air pollution and chemicals). Ten principal components explained 45% and 39% of the total variance in the pregnancy and childhood exposome, respectively, while 65 and 90 components were required to explain 95% of the exposome variability. Correlations between maternal (pregnancy) and childhood exposures were high (>0.6) for most exposures modeled at the residential address (e.g. air pollution), but were much lower and even close to zero for some chemical exposures. In conclusion, the early life exposome was high dimensional, meaning that it cannot easily be measured by or reduced to fewer components. Correlations between exposures from different exposure groups were much lower than within exposure groups, which have important implications for co-exposure confounding in multiple exposure studies. Also, we observed the early life exposome to be variable over time and to vary by cohort, so measurements at one time point or one place will not capture its complexities.


Can We Apply an Emotional Competence Measure to an Eastern Population? Psychometric Properties of the Profile of Emotional Competence in a Japanese Population.
Researchers have repeatedly argued that it is important to determine whether the psychometric properties of an emotional competence measure hold in Eastern populations because there may be cultural variability in abilities linked with emotional competence. However, few studies have examined potential differences in an emotional competence measure in Eastern cultures. To fill this gap, we investigated the applicability of the Profile of Emotional Competence to a Japanese population. Results demonstrated measurement and structural invariance across our Japanese and the original Belgian data sets. As was found in the Belgian sample, this measure showed adequate convergent and criterion validity in the Japanese sample. Furthermore, the scores on this measure were stronger predictors of subjective health and happiness in the Japanese than Belgian population. This measure also showed incremental validity. Our results suggest that the Profile of Emotional Competence is applicable to the Japanese population, an Eastern society.


Geometric optics analysis of modal propagation in graded-index cylindrical fiber.
Methods of geometric optics are used to characterize a multimode optical fiber. The discrete propagation modes are derived by applying the phase resonance constraint to equations of constant phase surfaces. This constraint provides a very clear geometrical interpretation of discrete propagation modes, and provides a link between the well known Wentzel, Kramers, Brillouin (WKB) method and geometric optics.


Remembering "primed" words: A counter-intuitive effect of repetition on recognition memory.
The present study examines the effect of immediate repetition on recognition memory. In a series of 4 experiments, the study phase task was to name aloud a word that was immediately preceded by either the same word (repeated trials) or a different word (not-repeated trials). Across experiments, performance in the study phase demonstrated the anticipated benefit in naming times for repeated trials. More important, performance in the test phase revealed greater sensitivity for not-repeated than repeated trials. This effect was observed even when repetitions at study were separated by an unrelated word (Experiment 3), and was eliminated only when participants named both words in succession at study (Experiment 4). These findings fit nicely with the desirable difficulty principle (R. A. Bjork, 1994), as they demonstrate that items more easily processed at study (i.e., repeated items) are not as well-encoded as items that are more difficult to process at study (i.e., not-repeated items). Furthermore, the current study points to the possibility that attentional orienting in response to processing difficulty may constitute a broadly important cognitive control adaptation that impacts memory encoding. (PsycINFO Database Record


Frontal and subcortical contribution to visual hallucinations in dementia with Lewy bodies and Parkinson's disease.
Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson's disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia. Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones. Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH. Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.


Migration in Afro-Brazilian rural communities: crossing demographic and genetic data.
Many studies have used genetic markers to understand global migration patterns of our species. However, there are only few studies of human migration on a local scale. We, therefore, researched migration dynamics in three Afro-Brazilian rural communities, using demographic data and ten Ancestry Informative Markers. In addition to the description of migration and marriage structures, we carried out genetic comparisons between the three populations, as well as between locals and migrants from each community. Genetic admixture analyses were conducted according to the gene-identity method, with Sub-Saharan Africans, Amerindians, and Europeans as parental populations. The three analyzed Afro-Brazilian rural communities consisted of 16% to 30% of migrants, most of them women. The age pyramid revealed a gap in the segment of men aged between 20 to 30 yrs. While endogamous marriages predominated, exogamous marriages were mainly patrilocal. Migration dynamics are apparently associated with matrimonial customs and other social practices of such communities. The impact of migration upon the populations' genetic composition was low but showed an increase in European alleles with a concomitant decrease in the Amerindian contribution. Admixture analysis evidenced a higher African contribution to the gene pool of the studied populations, followed by the contribution of Europeans and Amerindians, respectively.


[The prevalence and structure of biliary tract diseases in the rural population of northern regions of Siberia].
Biliary tracts were investigated in 3420 migrants and 1445 aborigines (Evens, Evenkis) living in Evenkia and Yakutia. Acalculous chronic cholecystitis and cholelithiasis were found in 8.5 and 8.8% of the migrants, respectively. In aborigines these diseases occurred in 4.5 and 1.5%, respectively. The risk to develop biliary disease for migrants grows after 4-5 years of stay in the Far North. It is concluded that biliary pathology in the Far North population was related to ethnic and geographical factors.