Effects of Sublethal Fungicides on Mutation Rates and Genomic Variation in Fungal Plant Pathogen, Sclerotinia sclerotiorum.
Pathogen exposure to sublethal doses of fungicides may result in mutations that may represent an important and largely overlooked mechanism of introducing new genetic variation into strictly clonal populations, including acquisition of fungicide resistance. We tested this hypothesis using the clonal plant pathogen, Sclerotinia sclerotiorum. Nine susceptible isolates were exposed independently to five commercial fungicides with different modes of action: boscalid (respiration inhibitor), iprodione (unclear mode of action), thiophanate methyl (inhibition of microtubulin synthesis) and azoxystrobin and pyraclostrobin (quinone outside inhibitors). Mycelium of each isolate was inoculated onto a fungicide gradient and sub-cultured from the 50-100% inhibition zone for 12 generations and experiment repeated. Mutational changes were assessed for all isolates at six neutral microsatellite (SSR) loci and for a subset of isolates using amplified fragment length polymorphisms (AFLPs). SSR analysis showed 12 of 85 fungicide-exposed isolates had a total of 127 stepwise mutations with 42 insertions and 85 deletions. Most stepwise deletions were in iprodione- and azoxystrobin-exposed isolates (n = 40/85 each). Estimated mutation rates were 1.7 to 60-fold higher for mutated loci compared to that expected under neutral conditions. AFLP genotyping of 33 isolates (16 non-exposed control and 17 fungicide exposed) generated 602 polymorphic alleles. Cluster analysis with principal coordinate analysis (PCoA) and discriminant analysis of principal components (DAPC) identified fungicide-exposed isolates as a distinct group from non-exposed control isolates (PhiPT = 0.15, P = 0.001). Dendrograms based on neighbor-joining also supported allelic variation associated with fungicide-exposure. Fungicide sensitivity of isolates measured throughout both experiments did not show consistent trends. For example, eight isolates exposed to boscalid had higher EC50 values at the end of the experiment, and when repeated, only one isolate had higher EC50 while most isolates showed no difference. Results of this support the hypothesis that sublethal fungicide stress increases mutation rates in a largely clonal plant pathogen under in vitro conditions. Collectively, this work will aid our understanding how non-lethal fungicide exposure may affect genomic variation, which may be an important mechanism of novel trait emergence, adaptation, and evolution for clonal organisms.


Enhancing the Charge Separation in Nanocrystalline Cu2ZnSnS4 Photocathodes for Photoelectrochemical Application: The Role of Surface Modifications.
Cu2ZnSnS4 (CZTS) colloidal inks were employed to prepare thin-film photocathodes that served as a model system to interrogate the effect of different surface treatments, viz. CdS, CdSe, and ZnSe buffer layers along with methylviologen (MV) adsorption, on the photoelectrochemical (PEC) performance using aqueous Eu(3+) redox electrolyte. PEC experiments revealed that ZnSe and CdSe overlayers outperform traditional CdS, and the additional surface modification with MV was found to further boost the charge extraction. By analyzing the photocurrent onset behavior and measuring the open circuit photopotentials, insights are gained into the nature of the observed improvements. While a more favorable conduction band offset rationalizes the improvement offered by CdSe, charge transfer through midgap states is invoked for ZnSe. Improvement offered by MV treatment is clearly caused by both the shifting of the flat-band potential and a charge-transfer mediation effect. Overall, this work suggests promising alternative surface treatments for CZTS photocathodes for PEC energy conversion.


FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage.
DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM-Chk2-p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM-Chk2-p53-mediated apoptotic programme following DNA damage.


Jumping-based Asymmetries are Negatively Associated with Jump, Change of Direction, and Repeated Sprint Performance, but not Linear Speed, in Adolescent Handball Athletes.
The aim of the present study was to determine the association of multi-directional jumping asymmetries with measures of physical performance. Forty-two youth handball athletes (age: 16.0 ± 1.3 years; body height: 174.11 ± 7.3 cm; body mass: 70.49 ± 13.3 kg) performed a mid-season fitness test battery consisting of single leg countermovement, lateral and broad jump tests, two change of direction speed (CODS) tests, an 8 x 10 m repeated sprint test, and a 20 m sprint. The Kappa coefficient showed only 'slight' levels of agreement (K range = -0.05 to 0.15), indicating that asymmetries rarely favoured the same side during each of the jump tests. The single leg countermovement jump showed significantly (p = 0.006) larger asymmetries (11.2 ± 8.4) than the broad jump (6.4 ± 4.6) and significant correlations were present between jumping asymmetries and jump (r = -0.32 to -0.52), CODS (r = 0.31 to 0.32) and repeated sprint (r = 0.35 to 0.40) performance. The findings of the present study highlight the independent nature of jumping asymmetries and associations with measures of physical performance. Practitioners are encouraged to use multiple tests to detect existing side differences and consider appropriate training interventions for the reduction of inter-limb asymmetries.


A Randomized, Clinical Trial of Preadmission Chlorhexidine Skin Preparation for Lower Extremity Total Joint Arthroplasty.
Periprosthetic infections are devastating postoperative complications of total joint arthroplasty (TJA), with native skin flora commonly identified as causative organisms. We compared 2% chlorhexidine gluconate-impregnated cloths to standard-of-care antiseptic bathing in patients before TJA, to evaluate periprosthetic infection risk at 1-year follow-up. This was a prospective, randomized, controlled trial at a single institution of patients undergoing hip or knee arthroplasty. Chlorhexidine-treated patients (275 arthroplasties) applied 2% chlorhexidine gluconate-impregnated cloths the night before and morning of admission. The standard-of-care cohort (279 arthroplasties) bathed with soap and water preadmission. Patients were excluded according to the following: (1) unable to comply with study requirements, (2) pregnant, (3) <18 years, (4) medical history of immunosuppression or steroid use, (5) chronic hepatitis B/C infection, (6) had infection around joint requiring surgery, or (7) chose not to participate. A total of 539 patients (554 arthroplasties) were included in the final population. There were no significant differences in American Society of Anesthesiologists grade, cut time, risk scores, or diabetes and smoking prevalence between cohorts (P > .05). A lower periprosthetic infection rate was found in the chlorhexidine cohort (0.4%) when compared to standard-of-care cohorts (2.9%). The infection odds ratio was 8.15 (95% confidence interval = 1.01-65.6; P = .049) for the standard-of-care cohort compared to the chlorhexidine cohort. No differences in assessed risk factors were found between groups. No severe adverse events were observed. Preoperative chlorhexidine cloth use decreased the risk of periprosthetic infection. This may be an appropriate antiseptic protocol to implement for patients undergoing lower extremity TJA.


Background rates of adverse pregnancy outcomes for assessing the safety of maternal vaccine trials in sub-Saharan Africa.
Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa. We developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed. Accounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6-73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9-16.4) or premature (median 15.4%, IQR: 10.6-19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5-17.6), with the musculoskeletal system comprising 30%. Some clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.


Combination of short-read, long-read, and optical mapping assemblies reveals large-scale tandem repeat arrays with population genetic implications.
Accurate and contiguous genome assembly is key to a comprehensive understanding of the processes shaping genomic diversity and evolution. Yet, it is frequently constrained by constitutive heterochromatin, usually characterized by highly repetitive DNA. As a key feature of genome architecture associated with centromeric and subtelomeric regions, it locally influences meiotic recombination. In this study, we assess the impact of large tandem repeat arrays on the recombination rate landscape in an avian speciation model, the Eurasian crow. We assembled two high-quality genome references using single-molecule real-time sequencing (long-read assembly [LR]) and single-molecule optical maps (optical map assembly [OM]). A three-way comparison including the published short-read assembly (SR) constructed for the same individual allowed assessing assembly properties and pinpointing misassemblies. By combining information from all three assemblies, we characterized 36 previously unidentified large repetitive regions in the proximity of sequence assembly breakpoints, the majority of which contained complex arrays of a 14-kb satellite repeat or its 1.2-kb subunit. Using whole-genome population resequencing data, we estimated the population-scaled recombination rate (ρ) and found it to be significantly reduced in these regions. These findings are consistent with an effect of low recombination in regions adjacent to centromeric or subtelomeric heterochromatin and add to our understanding of the processes generating widespread heterogeneity in genetic diversity and differentiation along the genome. By combining three different technologies, our results highlight the importance of adding a layer of information on genome structure that is inaccessible to each approach independently.


Experimental and Numerical Investigation of Parameters Affecting High-Frequency Irreversible Electroporation for Prostate Cancer Ablation.
While the primary goal of focal therapy for prostate cancer (PCa) is conserving patient quality of life by reducing oncological burden, available modalities use thermal energy or whole-gland radiation which can damage critical neurovascular structures within the prostate and increase risk of genitourinary dysfunction. High-frequency irreversible electroporation (H-FIRE) is a promising alternative ablation modality that utilizes bursts of pulsed electric fields (PEFs) to destroy aberrant cells via targeted membrane damage. Due to its nonthermal mechanism, H-FIRE offers several advantages over state-of-the-art treatments, but waveforms have not been optimized for treatment of PCa. In this study, we characterize lethal electric field thresholds (EFTs) for H-FIRE waveforms with three different pulse widths as well as three interpulse delays in vitro and compare them to conventional irreversible electroporation (IRE). Experiments were performed in non-neoplastic and malignant prostate cells to determine the effect of waveforms on both targeted (malignant) and adjacent (non-neoplastic) tissue. A numerical modeling approach was developed to estimate the clinical effects of each waveform including extent of nonthermal ablation, undesired thermal damage, and nerve excitation. Our findings indicate that H-FIRE waveforms with pulse durations of 5 and 10 μs provide large ablations comparable to IRE with tolerable levels of thermal damage and minimized muscle contractions. Lower duration (2 μs) H-FIRE waveforms exhibit the least amount of muscle contractions but require increased voltages which may be accompanied by unwanted thermal damage.


Real time calorimetric characterisation of clay - drug complex dispersions and particles.
Isothermal titration calorimetry (ITC) along with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX) and high-performance liquid chromatography (HPLC) were employed to investigate the process of adsorption of propranolol hydrochloride (PPN) onto magnesium aluminium silicate (MAS) and to characterise the MAS-PPN particles formed upon complexation. The composition of MAS was confirmed by infrared (IR) spectroscopy and a calcimeter. The calorimetric results confirmed the binding between PPN and MAS at various pHs and temperatures. The overall change in enthalpy was found to be exothermic with a comparatively small entropic contribution to the total change in Gibbs free energy. These findings suggest that the binding process was enthalpically driven and entropically unfavourable (lower affinity) suggesting hydrogen bonding and electrostatic interactions dominating the interaction. The variation of pH and temperature did not have a great impact on the thermodynamics of the binding process, as observed from the similarity in enthalpy (ΔH), entropy (ΔS) or Gibbs free energy (ΔG). A slight reduction in the binding affinity (Ka) with varing pH and temperature was however observed. SEM/EDX studies showed the occurrence of changes in the microstructural properties of MAS following complexation which may explain the potential of MAS-PPN complexes for controlled drug release promoting pharmaceutical innovation.


A finite state model for respiratory motion analysis in image guided radiation therapy.
Effective image guided radiation treatment of a moving tumour requires adequate information on respiratory motion characteristics. For margin expansion, beam tracking and respiratory gating, the tumour motion must be quantified for pretreatment planning and monitored on-line. We propose a finite state model for respiratory motion analysis that captures our natural understanding of breathing stages. In this model, a regular breathing cycle is represented by three line segments, exhale, end-of-exhale and inhale, while abnormal breathing is represented by an irregular breathing state. In addition, we describe an on-line implementation of this model in one dimension. We found this model can accurately characterize a wide variety of patient breathing patterns. This model was used to describe the respiratory motion for 23 patients with peak-to-peak motion greater than 7 mm. The average root mean square error over all patients was less than 1 mm and no patient has an error worse than 1.5 mm. Our model provides a convenient tool to quantify respiratory motion characteristics, such as patterns of frequency changes and amplitude changes, and can be applied to internal or external motion, including internal tumour position, abdominal surface, diaphragm, spirometry and other surrogates.


Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants.
DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases. This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age. Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussis filamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures. The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.


Acute Appendicitis Is Associated with Peptic Ulcers: A Population-based Study.
Despite some studies having indicated a possible association between appendicitis and duodenal ulcers, this association was mainly based on regional samples or limited clinician experiences, and as such, did not permit unequivocal conclusions. In this case-control study, we examined the association of acute appendicitis with peptic ulcers using a population-based database. We included 3574 patients with acute appendicitis as cases and 3574 sex- and age-matched controls. A Chi-squared test showed that there was a significant difference in the prevalences of prior peptic ulcers between cases and controls (21.7% vs. 16.8%, p < 0.001). The adjusted odds ratio (OR) of prior peptic ulcers for cases was 1.40 (95% confidence interval [CI]: 1.24~1.54, p < 0.001) compared to controls. The results further revealed that younger groups demonstrated higher ORs for prior peptic ulcers among cases than controls. In particular, the adjusted OR for cases < 30 years old was as high as 1.65 (95% CI = 1.25~2.19; p < 0.001) compared to controls. However, we failed to observe an association of acute appendicitis with peptic ulcers in the ≥ 60-year age group (OR = 1.19, 95% CI = 0.93~1.52). We concluded that there is an association between acute appendicitis and a previous diagnosis of peptic ulcers.


Ontogeny of adrenal steroid hydroxylases: evidence for cAMP-independent gene expression.
Total RNA from normal and anencephalic human fetal adrenals was examined by blot analysis for transcripts encoding P-450scc, P-450(11) beta, P-450(17) alpha, P-450C21 and adrenodoxin using bovine cDNA clones specific for these different enzymes. The specific contents of RNA encoding these components of the adrenocortical steroidogenic pathway were found to be similar in both types of adrenal tissue. Likewise, immunoblot analysis showed comparable concentrations of P-450scc, P450(17) alpha and adrenodoxin protein to be present in adrenal tissues from normal and anencephalic human fetuses. Immunoblot analysis of homogenates of fetal sheep adrenals of increasing gestational age (85-145 days) showed constant levels of P-450scc and P-450(11) beta, but increasing P-450(17) alpha content, especially near term. Both sheep fetuses prior to 136 days gestational age and human anencephalic fetuses are known to have extremely low circulating levels of immunoreactive ACTH as well as very low adrenal adenylate cyclase activity. Thus, it is concluded that factors other than pituitary ACTH which operate independent of adenylate cyclase activation are required for the initial expression (imprinting) of steroid hydroxylase genes.


Current evidence and future research needs for FeNO measurement in respiratory diseases.
Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.


Inactivation of F-specific bacteriophages during flocculation with polyaluminum chloride - a mechanistic study.
Bacteriophages are often used as surrogates for enteric viruses in spiking experiments to determine the efficiencies of virus removal of certain water treatment measures, like e.g. flocculation or filtration steps. Such spiking experiments with bacteriophages are indispensable if the natural virus concentrations in the raw water of water treatment plants are too low to allow the determination of elimination levels over several orders of magnitude. In order to obtain reliable results from such spiking tests, it is essential that bacteriophages behave comparable to viruses and remain stable during the experiments. To test this, the influence of flocculation parameters on the bacteriophages MS2, Qβ and phiX174 was examined. Notably, the F-specific phages MS2 and Qβ were found to be inactivated in flocculation processes with polyaluminum chloride (PACl). In contrast, other aluminum coagulants like AlCl3 or Al2(SO4)3 did not show a comparable effect on MS2 in this study. In experiments testing the influence of different PACl species on MS2 and Qβ inactivation during flocculation, it could be shown that cationic dissolved PACl species (Al13) interacted with the MS2 surface and hereby reduced the surviving phage fraction to c/c0 values below 1*10(-4) even at very low PACl concentrations of 7 μmol Al/L. Other inactivation mechanisms like the irreversible adsorption of phages to the floc structure or the damage of phage surfaces due to entrapment into the floc during coagulation and floc formation do not seem to contribute to the low surviving fraction found for both F-specific bacteriophages. Furthermore, no influence of phage agglomeration or pH drops during the flocculation process on phage inactivation could be observed. The somatic coliphage phiX174 in contrast did not show sensitivity to chemical stress and in accordance only slight interaction between Al13 and the phage surface was observed. Consequently, F-specific phages like MS2 should not be used as surrogate for viruses in flocculation experiments with PACl to determine the removal rates of viruses, as the results are influenced by a strong inactivation of the bacteriophages due to the experimental conditions.


Diastolic fourth and fifth phase blood pressure in 10-15-year-old children. The Children and Adolescent Blood Pressure Program.
Measurement of diastolic blood pressure is complicated by the presence of two diastolic Korotkoff phases (fourth phase and fifth phase) in many children and adults. In the present study, diastolic fourth phase and diastolic fifth phase were evaluated in 1986-1987 in 19,274 Minneapolis-St. Paul school children aged 10-15 years. Approximately 50 percent of the children had no difference between fourth phase and fifth phase (i.e., fourth phase - fifth phase = 0) and 15 percent had a difference of only 1-4 mmHg. However, the fourth phase - fifth phase difference was 5-10 mmHg in 20 percent, 11-20 mmHg in 11 percent and greater than 21 mmHg in 3 percent of the children. Statistical analyses showed that the fourth phase - fifth phase difference tended to be greater in boys than girls and in older than younger children, was positively related to height, systolic blood pressure and fourth phase blood pressure, and negatively related to body mass index and fifth phase blood pressure. Using fifth phase instead of fourth phase in 10-12-year-old children and fourth phase instead of fifth phase in 13-15-year-old children to define diastolic blood pressures significantly changed the prevalence for significant diastolic hypertension by 2-3 percent.


Reading training with threshold stimuli in people with central vision loss: a feasibility study.
To evaluate the effectiveness of a perceptual learning technique for improving reading performance of patients with central vision loss and to explore whether this learning generalizes to other visual functions. Ten patients with central vision loss were trained binocularly, in four consecutive sessions, with serially presented words printed at each patient's reading acuity limit. Patients read 10 blocks of 100 words in each session. They were encouraged to read the whole word and were discouraged to read letter by letter. Assessment sessions before and after training measured fixation stability, monocular and binocular visual acuity, as well as reading acuity, critical print size, and maximum reading speed with continuous text. Another six patients with central vision loss were included in a test-retest control group and were tested twice, 1 week apart, with no intervention. The average time required to read a block of trials decreased significantly with each training session. After training, continuous text reading improved in terms of reading acuity (p = 0.017) and maximum reading speed (p = 0.01), but critical print size did not change. Binocular acuity improved significantly from an average of 0.54 logMAR before training to 0.44 logMAR after training. Binocular ratio (better eye acuity/binocular acuity) increased from an average of 1.0 before training to 1.17 after training. There was a 62% improvement in fixation stability in the better eye and 58% in the worse eye. There were no changes in the outcome measures for the test-retest control group. The technique described in this article can be used for vision rehabilitation of patients with central vision loss. When training is done with size threshold stimuli, learning generalizes to visual acuity, continuous text reading, and fixation stability.


Effectiveness of pneumococcal conjugate vaccine against hospital admissions for pneumonia in Australian children: a retrospective, population-based, record-linked cohort study.
Reductions in pneumonia hospitalisations following introduction of pneumococcal conjugate vaccines (PCVs) have been reported from high-incidence and low-incidence settings but long-term data comparing vaccinated with unvaccinated children are sparse. We did a retrospective, population-based, record-linkage cohort study in Australian children using administrative health data from the Western Australian Midwives' Notification System and New South Wales Perinatal Data Collection, and the birth and death registries in both states. PCV vaccination details, pneumonia-coded hospital admissions, and invasive pneumococcal disease notification records were individually linked for children born between 2001 and 2012. The primary outcome was defined as the first hospital admission for all-cause pneumonia. Cox models were used to calculate adjusted hazard ratios (HR) to estimate the effect of PCV doses on pneumonia-coded hospital admissions by Aboriginal status, birth period, remoteness, and pneumonia diagnostic category in children younger than 2 years. Person-time of follow-up time for each child started at birth and was censored at the earliest of first hospital admission for all-cause pneumonia, death, invalid PCV dose, when the child reached age 24 months, or the end date of the study period (Dec 31, 2013) FINDINGS: The study cohort comprised 1 365 893 children liveborn between Jan 1, 2001, and Dec 31, 2012, of whom 66 484 (4·9%) were identified as Aboriginal. The overall rate for all-cause pneumonia hospital admissions for children younger than 2 years over the entire study period was 17·6/1000 child-years in Aboriginal children and 5·5/1000 child-years in non-Aboriginal children. Compared with children born between 2001 and 2004 (ie, the pre-universal PCV period), the incidence of pneumonia-coded hospital admissions decreased in both vaccinated (6·5 vs 5·7 per 1000 child-years [12% reduction, 95% CI 3-21; p=0·01]) and unvaccinated non-Aboriginal children (6·8 vs 3·7 [45% reduction; 41-49]) born 2005-12 (the universal PCV period); among Aboriginal children, declines were significant only among those vaccinated (27·4 vs 14·1 [49% reduction, 40-55]). Among Aboriginal children born 2005-12, the risk of pneumonia-coded hospital admission after three doses of PCV was lower than those unvaccinated (adjusted HR 0·83, 95% CI 0·65-0·99) but, among non-Aboriginal children, the risk was similar (adjusted HR 1·09, 0·98-1·22). Overall, remote-born Aboriginal children had the highest incidence of hospital admission for pneumonia and among children born 2005-12, the adjusted risk was 37% lower (adjusted HR 0·63, 95% CI 0·42-0·96) among those fully vaccinated than those unvaccinated. Reductions in pneumonia-coded hospital admissions in unvaccinated children predominated in non-Aboriginal children with low incidence of pneumonia but were not significant in Aboriginal children with high incidence. These findings have potential implications for measuring PCV effect using a non-specific endpoint such as all-cause pneumonia in high-incidence populations. Commonwealth Government Collaborative Research Infrastructure Strategy and Education Investment Fund Super Science Initiative and the Australian National Health and Medical Research Council.


BOSTN Bundle Intervention for Perioperative Screening and Management of Patients With Suspected Obstructive Sleep Apnea: A Hospital Registry Study.
We developed and implemented a perioperative guideline for obstructive sleep apnea (OSA), comprising a preoperative screening tool (BOSTN) and clinical management pathways. OSA was suspected with 2 or more of the following: body mass index ≥30 kg/m, observed apnea, loud snoring, daytime tiredness, and neck circumference ≥16.5 inches in women or ≥ 17.5 inches in men. The primary objective of this study was to assess the association between high BOSTN scores and the requirement of invasive mechanical ventilation after surgery. In this hospital registry study, 169,662 noncardiac surgical cases performed at Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, between May 2008 and September 2017 were analyzed. We assessed the association between a high BOSTN Score (score ≥2) and the primary outcome of requirement of invasive mechanical ventilation within 7 days after surgery using multivariable logistic regression adjusted for patient-specific factors and case-specific surgical and anesthesiological confounders. Patients with a BOSTN Score ≥2 were assumed to have a high likelihood of suffering from OSA. Key secondary outcome was postoperative desaturation, defined as a peripheral oxygen saturation measurement <90% within 10 minutes of extubation. Invasive mechanical ventilation within 7 days of surgery was necessary in 3170 (2.3%) low-risk cases (BOSTN Score <2) and 664 (2.1%) high-risk cases (BOSTN Score ≥2). A score ≥2 was associated with significantly lower odds of requiring postoperative invasive ventilation (adjusted odds ratio [aOR], 0.89; 95% confidence interval [CI], 0.80-0.98; P = .017), but with an increased risk of postextubation desaturation (aOR, 1.34; 99.3% CI, 1.21-1.48; P < .001). Patients with a score ≥2 were hospitalized for an average of 3.71 days after surgery, compared to 4.27 days with a score <2 (adjusted incidence rate ratio [aIRR], 0.87; 99.3% CI, 0.84-0.91; P < .001). Patients at high risk of OSA required postoperative mechanical ventilation less frequently, had higher odds of postoperative desaturation, and were hospitalized for shorter periods of time.


Variable glutathione levels and expression of antioxidant enzymes in human endothelial cells.
We have investigated the relationship between intracellular glutathione levels and the inducibility of the mRNAs encoding the major antioxidant enzymes Cu,Zn superoxide dismutase (Cu,Zn SOD), catalase (CAT), glutathione peroxidase (GP), and the stress protein heme oxygenase (HO) following exposure of human umbilical vein endothelial cells (HUVEC) to either hypoxanthine-xanthine oxidase or 95% O2. Treatment of HUVEC with 2 and 200 microM buthionine sulfoximine (BSO) for 16 h reduced total glutathione (GSH) levels by 51 and 95%, respectively, whereas treatment with 100 microM diethylmaleate (DEM) for 24 h increased the cellular GSH content by 58%. None of these treatments affected the responsiveness of HUVEC to a subsequent oxidant challenge, in terms of antioxidant enzymes activities and mRNA levels. On the contrary, HO mRNA was significantly induced by both BSO and DEM, as well as by hyperoxia, albeit to a different extent. We conclude that intracellular redox changes do not appear to regulate the expression of the mRNAs encoding Cu,Zn SOD, CAT, and GP. Furthermore, factors other than endogenous thiols may play a role in the control of HO mRNA expression.


Molecular diversity, population structure, and linkage disequilibrium in a worldwide collection of tobacco (Nicotiana tabacum L.) germplasm.
The goals of our study were to assess the phylogeny and the population structure of tobacco accessions representing a wide range of genetic diversity; identify a subset of accessions as a core collection capturing most of the existing genetic diversity; and estimate, in the tobacco core collection, the extent of linkage disequilibrium (LD) in seven genomic regions using simple sequence repeat (SSR) markers. To this end, a collection of accessions were genotyped with SSR markers. Molecular diversity was evaluated and LD was analyzed across seven regions of the genome. A genotyping database for 312 tobacco accessions was profiled with 49 SSR markers. Principal Coordinate Analysis (PCoA) and Bayesian cluster analysis revealed structuring of the tobacco population with regard to commercial classes and six main clades were identified, which correspond to "Oriental", Flue-Cured", "Burley", "Dark", "Primitive", and "Other" classes. Pairwise kinship was calculated between accessions, and an overall low level of co-ancestry was observed. A set of 89 genotypes was identified that captured the whole genetic diversity detected at the 49 loci. LD was evaluated on these genotypes, using 422 SSR markers mapping on seven linkage groups. LD was estimated as squared correlation of allele frequencies (r2). The pattern of intrachromosomal LD revealed that in tobacco LD extended up to distances as great as 75 cM with r2 > 0.05 or up to 1 cM with r2 > 0.2. The pattern of LD was clearly dependent on the population structure. A global population of tobacco is highly structured. Clustering highlights the accessions with the same market class. LD in tobacco extends up to 75 cM and is strongly dependent on the population structure.


Multiclass Classification of Agro-Ecological Zones for Arabica Coffee: An Improved Understanding of the Impacts of Climate Change.
Cultivation of Coffea arabica is highly sensitive to and has been shown to be negatively impacted by progressive climatic changes. Previous research contributed little to support forward-looking adaptation. Agro-ecological zoning is a common tool to identify homologous environments and prioritize research. We demonstrate here a pragmatic approach to describe spatial changes in agro-climatic zones suitable for coffee under current and future climates. We defined agro-ecological zones suitable to produce arabica coffee by clustering geo-referenced coffee occurrence locations based on bio-climatic variables. We used random forest classification of climate data layers to model the spatial distribution of these agro-ecological zones. We used these zones to identify spatially explicit impact scenarios and to choose locations for the long-term evaluation of adaptation measures as climate changes. We found that in zones currently classified as hot and dry, climate change will impact arabica more than those that are better suited to it. Research in these zones should therefore focus on expanding arabica's environmental limits. Zones that currently have climates better suited for arabica will migrate upwards by about 500m in elevation. In these zones the up-slope migration will be gradual, but will likely have negative ecosystem impacts. Additionally, we identified locations that with high probability will not change their climatic characteristics and are suitable to evaluate C. arabica germplasm in the face of climate change. These locations should be used to investigate long term adaptation strategies to production systems.


How to use a systematic literature review and meta-analysis.
This article introduces practicing urologists to the critical appraisal of systematic reviews and meta-analyses to guide their evidence-based clinical practice. Using a urological clinical case scenario we introduce a 3-step process in evaluating systematic reviews and meta-analyses by considering 1) the validity of the review results, 2) what the results are, and 3) the extent to which the results can and should be applied to patient care. A systematic review seeks to synthesize the medical literature about a specific clinical question using explicit methods to perform a comprehensive literature search, identify and select eligible studies, critically appraise their methods, and judiciously summarize the results considering how they vary with study characteristics. When this summary involves statistical methods, ie a meta-analysis, reviewers can offer a pooled estimate that will have greater precision and will apply more broadly than the individual studies. The quality of the underlying studies, the consistency of results across studies and the precision of the pooled estimate can considerably affect the strength of inference from systematic reviews. Valid systematic reviews of high quality studies can increase the confidence with which urologists and patients make evidence-based decisions. Thus, urologists need to recognize the inherent limitations, understand the results and apply them judiciously to patient care.


A comprehensive analysis of hearing preservation after radiosurgery for vestibular schwannoma.
Gamma Knife surgery (GKS) has evolved into a practical alternative to open microsurgical resection in the treatment of patients with vestibular schwannoma (VS). Hearing preservation rates in GKS series suggest very favorable outcomes without the possible acute morbidity associated with open microsurgery. To mitigate institutional and practitioner bias, the authors performed an analytical review of the published literature on the GKS treatment of vestibular schwannoma patients. Their aim was to objectively characterize the prognostic factors that contribute to hearing preservation after GKS, as well as methodically summarize the reported literature describing hearing preservation after GKS for VS. A comprehensive search of the English-language literature revealed a total of 254 published studies reporting assessable and quantifiable outcome data obtained in patients who underwent radiosurgery for VSs. Inclusion criteria for articles were 4-fold: 1) hearing preservation rates reported specifically for VS; 2) hearing status reported using the American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) or Gardner-Robertson classification; 3) documentation of initial tumor size; and 4) GKS was the only radiosurgical modality in the treatment. In the analysis only patients with AAO-HNS Class A or B or Gardner-Robertson Grade I or II status at the last follow-up visit were defined as having preserved hearing. Hearing preservation and outcome data were then aggregated and analyzed based on the radiation dose, tumor volume, and patient age. The 45 articles that met the authors' inclusion criteria represented 4234 patients in whom an overall hearing preservation rate was 51%, irrespective of radiation dose, patient age, or tumor volume. Practitioners who delivered an average < or = 13-Gy dose of radiation reported a higher hearing preservation rate (60.5% at < or = 13 Gy vs 50.4% at > 13 Gy; p = 0.0005). Patients with smaller tumors (average tumor volume < or = 1.5 cm(3)) had a hearing preservation rate (62%) comparable with patients harboring larger tumors (61%) (p = 0.8968). Age was not a significant prognostic factor for hearing preservation rates as in older patients there was a trend toward improved hearing preservation rates (56% at < 65 years vs 71% at > or = 65 years of age; p < 0.1134). The average overall follow-up in the studies reviewed was 44.4 +/- 32 months (median 35 months). These data provide a methodical overview of the literature regarding hearing preservation with GKS for VS and a less biased assessment of outcomes than single-institution studies. This objective analysis provides insight into advising patients of hearing preservation rates for GKS treatment of VSs that have been reported, as aggregated in the published literature. Analysis of the data suggests that an overall hearing preservation rate of approximately 51% can be expected approaching 3-4 years after radiosurgical treatment, and the analysis reveals that patients treated with < or = 13 Gy were more likely to have preserved hearing than patients receiving larger doses of radiation. Furthermore, larger tumors and older patients do not appear to be at any increased risk for hearing loss after GKS for VS than younger patients or patients with smaller tumors.


[Nematodes of the genus Oesophagostomum: an emerging risk for humans and apes in Africa?].
Nematodes of the genus Oesophagostomum are common intestinal parasites found in cattle, pigs and primates. They can cause severe illness, resulting from the formation of granulomas, caseous lesions and abscesses in the intestinal wall. Human oesophagostomosis is endemic in northern Ghana and Togo. In these regions, epidemiological investigations have been conducted to determine the biological characteristics, transmission dynamics and optimal management of clinical cases. Nodular oesophagostomosis has also been described in free-ranging chimpanzees and gorillas. Clinical signs associated with nodules have been observed in great apes raised in sanctuaries, while the health status of their wild counterparts does not seem to be significantly affected It has been suggested that some nonhuman primates may act as reservoirs for human oesophagostomosis. In Ghana, identification of genetic differences among Oesophagostomum nematodes infecting different primate hosts suggests that oesophagostomosis is a rare zoonosis. In Uganda, where the situation is diferent, cross-infection is probably more frequent.


Lithium Di- and trimethyl dimolybdenum(II) complexes with Mo-Mo quadruple bonds and bridging methyl groups.
New dimolybdenum complexes of composition [Mo2{μ-Me}2Li(S)}(μ-X)(μ-N^N)2] (3a-3c), where S = THF or Et2O and N^N represents a bidentate aminopyridinate or amidinate ligand that bridges the quadruply bonded molybdenum atoms, were prepared from the reaction of the appropriate [Mo2{μ-O2CMe}2(μ-N^N)2] precursors and LiMe. For complex 3a, X = MeCO2, while in 3b and 3c, X = Me. Solution NMR studies in C6D6 solvent support formulation of the complexes as contact ion pairs with weak agostic Mo-CH3···Li interactions, which were also evidenced by X-ray crystallography in the solid-state structures of the molecules of 3a and 3b. Samples of 3c enriched in (13)C (99%) at the metal-bonded methyl sites were also prepared and investigated by NMR spectroscopy employing C6D6 and THF-d8 solvents. Crystallization of 3c from toluene:tetrahydrofuran mixtures provided single crystals of the solvent separated ion pair complex [Li(THF)4] [Mo2(Me)2(μ-Me){μ-HC(NDipp)2}2] (4c), where Dipp stands for 2,6-iPr2C6H3. A computational analysis of the Mo2(μ-Me)2Li core of complexes 3a and 3b has been developed, which is consistent with a small but non-negligible electron-density sharing between the C and Li atoms of the mainly ionic CH3···Li interactions.


Xeroderma pigmentosum group C protein interacts with histones: regulation by acetylated states of histone H3.
In the mammalian global genome nucleotide excision repair pathway, two damage recognition factors, XPC and UV-DDB, play pivotal roles in the initiation of the repair reaction. However, the molecular mechanisms underlying regulation of the lesion recognition process in the context of chromatin structures remain to be understood. Here, we show evidence that damage recognition factors tend to associate with chromatin regions devoid of certain types of acetylated histones. Treatment of cells with histone deacetylase inhibitors retarded recruitment of XPC to sites of UV-induced DNA damage and the subsequent repair process. Biochemical studies showed novel multifaceted interactions of XPC with histone H3, which were profoundly impaired by deletion of the N-terminal tail of histone H3. In addition, histone H1 also interacted with XPC. Importantly, acetylation of histone H3 markedly attenuated the interaction with XPC in vitro, and local UV irradiation of cells decreased the level of H3K27ac in the damaged areas. Our results suggest that histone deacetylation plays a significant role in the process of DNA damage recognition for nucleotide excision repair and that the localization and functions of XPC can be regulated by acetylated states of histones.


Reprogramming is essential in nuclear transfer.
Fertile offspring have been produced by nuclear transfer from adult somatic cells in several mammalian species (Wilmut et al., 1997; Kato et al., 1998; Wakayama et al., 1998; Polejaeva et al., 2000; Chesne et al., 2002; Shin et al., 2002; Zhou et al., 2003). Various possible causes have been suggested for the overall low efficiency (Perry and Wakayama, 2002). Notably, however, it has not yet been clearly demonstrated whether reprogramming after nuclear transfer is necessary for successful cloning. Here we show that reprogramming is essential in nuclear transfer, by comparing the developmental efficiency after the transfer of cumulus cell nuclei with that for zygote nuclei. Nuclear transfers from blastomeres of a series of pre-implantation stages showed further that, as development proceeds, the nuclei progressively lose their potency and become more difficult to reprogram upon their transfer into enucleated MII oocytes. We also found that naturally ovulated oocytes are much better recipients of a nucleus than are superovulated oocytes, which have been used in all the nuclear transfer experiments reported so far. This indicates that cloning efficiency can also be increased to some extent by technical improvements. All these results enable us to distinguish more clearly between the inherent problem of reprogramming and technical problems associated with materials, manipulation, and in vitro culture.


Anisotropy of the monomer random walk in a polymer melt: local-order and connectivity effects.
The random walk of a bonded monomer in a polymer melt is anisotropic due to local order and bond connectivity. We investigate both effects by molecular-dynamics simulations on melts of fully-flexible linear chains ranging from dimers (M = 2) up to entangled polymers (M = 200). The corresponding atomic liquid is also considered a reference system. To disentangle the influence of the local geometry and the bond arrangements, and to reveal their interplay, we define suitable measures of the anisotropy emphasising either the former or the latter aspect. Connectivity anisotropy, as measured by the correlation between the initial bond orientation and the direction of the subsequent monomer displacement, shows a slight enhancement due to the local order at times shorter than the structural relaxation time. At intermediate times-when the monomer displacement is comparable to the bond length-a pronounced peak and then decays slowly as t (-1/2), becoming negligible when the displacement is as large as about five bond lengths, i.e. about four monomer diameters or three Kuhn lengths. Local-geometry anisotropy, as measured by the correlation between the initial orientation of a characteristic axis of the Voronoi cell and the subsequent monomer dynamics, is affected at shorter times than the structural relaxation time by the cage shape with antagonistic disturbance by the connectivity. Differently, at longer times, the connectivity favours the persistence of the local-geometry anisotropy, which vanishes when the monomer displacement exceeds the bond length. Our results strongly suggest that the sole consideration of the local order is not enough to understand the microscopic origin of the rattling amplitude of the trapped monomer in the cage of the neighbours.


Survival time and prognostic factors in cats with newly diagnosed diabetes mellitus: 114 cases (2000-2009).
To determine overall survival time and identify prognostic factors associated with survival time in cats with newly diagnosed diabetes mellitus. Retrospective case series. 114 cats with newly diagnosed diabetes mellitus. Data for analysis included history, signalment, physical examination findings, hematologic and serum biochemical data, presence of ketoacidosis, and diagnosis of concurrent diseases at initial evaluation. The effects of possible predictors on survival time were determined by calculating hazard ratios (HRs) and 95% confidence intervals (CIs). Median survival time of diabetic cats was 516 days (range, 1 to 3,468 days); 70%, 64%, and 46% lived longer than 3, 6, and 24 months, respectively. Survival time was significantly shorter for cats with higher creatinine concentrations, with a hazard of dying approximately 5% greater for each increase of 10 μg/dL in serum creatinine concentration (adjusted HR, 1.005; 95% CI, 1.003 to 1.007). Ketoacidosis was not significantly associated with survival time (HR, 1.02; 95% CI, 0.590 to 1.78). Cats with newly diagnosed diabetes mellitus had a fair to good prognosis. High serum creatinine concentration at diagnosis was associated with a poor outcome, likely because of the adverse effects of renal dysfunction. Ketoacidosis apparently was not associated with decreased survival time, suggesting that this complication should not necessarily be regarded as unfavorable.


Banting lecture 1990. Beta-cells in type II diabetes mellitus.
In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)


Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127(low) Treg Cells in Patients With Chronic Rheumatoid Arthritis.
Conflicting evidence exists regarding the suppressive capacity of Treg cells in the peripheral blood (PB) of patients with rheumatoid arthritis (RA). The aim of this study was to determine whether Treg cells are intrinsically defective in RA. Using a range of assays on PB samples from patients with chronic RA and healthy controls, CD3+CD4+CD25+CD127(low) Treg cells from the CD45RO+ or CD45RA+ T cell compartments were analyzed for phenotype, cytokine expression (ex vivo and after in vitro stimulation), suppression of Teff cell proliferation and cytokine production, suppression of monocyte-derived cytokine/chemokine production, and gene expression profiles. No differences between RA patients and healthy controls were observed with regard to the frequency of Treg cells, ex vivo phenotype (CD4, CD25, CD127, CD39, or CD161), or proinflammatory cytokine profile (interleukin-17 [IL-17], interferon-γ [IFNγ], or tumor necrosis factor [TNF]). FoxP3 expression was slightly increased in Treg cells from RA patients. The ability of Treg cells to suppress the proliferation of T cells or the production of cytokines (IFNγ or TNF) upon coculture with autologous CD45RO+ Teff cells and monocytes was not significantly different between RA patients and healthy controls. In PB samples from some RA patients, CD45RO+ Treg cells showed an impaired ability to suppress the production of certain cytokines/chemokines (IL-1β, IL-1 receptor antagonist, IL-7, CCL3, or CCL4) by autologous lipopolysaccharide-activated monocytes. However, this was not observed in all patients, and other cytokines/chemokines (TNF, IL-6, IL-8, IL-12, IL-15, or CCL5) were generally suppressed. Finally, gene expression profiling of CD45RA+ or CD45RO+ Treg cells from the PB revealed no statistically significant differences between RA patients and healthy controls. Our findings indicate that there is no global defect in either CD45RO+ or CD45RA+ Treg cells in the PB of patients with chronic RA.


The Neon Fruit Illusion: A Fresh Recipe for Colour Science Demonstrations.
At this year's European Conference on Visual Perception, we debuted a novel colour science demonstration-and visual illusion-for the Un mare di illusioni exhibition. Under carefully curated lighting conditions, cycling through different illuminant spectra, certain fruits and vegetables appear to glow and dim in an unchanging environment. Encouraged by the positive reactions it received, and the numerous and specific questions from conference delegates, we here describe what this illusion is, why we believe it may work, and how this particular low-cost setup may be assembled and demonstrated for the amazement of your friends, students, and members of the public.


Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit.
Colistin is an old antibiotic that has been reintroduced as salvage therapy in hospitalised patients because it is frequently the only agent active against Gram-negative bacteria. Various guidelines for colistin administration have led to confusion in establishing the appropriate dose, which has potential for adverse consequences including treatment failure or toxicity. The emergence and spread of colistin resistance has been documented in South Africa (SA), but no local information exists on how and why colistin is used in hospitals, and similarly, compliance with current dosing guidelines is unknown. To evaluate the current utilisation of colistin in SA hospitals, in order to identify stewardship opportunities that could enhance the appropriate use of this antibiotic. Electronic patient records of adult patients on intravenous (IV) colistin therapy for >72 hours in four private hospitals were retrospectively audited over a 10-month period (1 September 2015 - 30 June 2016). The following data were recorded: patient demographics, culture and susceptibility profiles, diagnosis, and indication for use. Compliance with six colistin process measures was audited: obtaining a culture prior to initiation, administration of a loading dose, administration of the correct loading dose, adjustments to maintenance dose according to renal function, whether colistin was administered in combination with another antibiotic, and whether de-escalation following culture and sensitivity results occurred. Outcome measures included effects on renal function, overall hospital mortality, intensive care unit length of stay (LoS), and hospital LoS. Records of 199 patients on IV colistin were reviewed. There was 99.0% compliance with obtaining a culture prior to antibiotic therapy, 93.5% compliance with prescription of a loading dose, and 98.5% compliance regarding prescription of colistin in combination with another agent. However, overall composite compliance with the six colistin stewardship process measures was 82.0%. Non-compliance related to inappropriate loading and maintenance doses, lack of adjustment according to renal function and lack of de-escalation following culture sensitivity was evident. Significantly shorter durations of treatment were noted in patients who received higher loading doses (p=0.040) and in those who received maintenance doses of 4.5 MU twice daily v. 3 MU three times daily (p=0.0027). In addition, compared with patients who survived, more patients who died received the 3 MU three times daily maintenance dose (p=0.0037; phi coefficient 0.26). The study identified multiple stewardship opportunities to optimise colistin therapy in hospitalised patients. Urgent implementation of a stewardship bundle to improve colistin utilisation is warranted.


Comparison of Low-Dose Higher-Relaxivity and Standard-Dose Lower-Relaxivity Contrast Media for Delayed-Enhancement MRI: A Blinded Randomized Crossover Study.
The gadolinium-based MRI contrast agent gadobenate dimeglumine has nearly twice the MR relaxivity of gadopentetate dimeglumine at 1.5 T. The purpose of this study was to determine whether a lower dose (0.1 mmol/kg) of gadobenate dimeglumine can be used to obtain delayed-enhancement MR images comparable to those obtained with a standard dose (0.2 mmol/kg) of gadopentetate dimeglumine. In this blinded randomized crossover study, 20 patients with known myocardial infarction underwent two separate delayed-enhancement MRI examinations after receiving 0.1 mmol/kg gadobenate dimeglumine and 0.2 mmol/kg gadopentetate dimeglumine (random administration). The conspicuity of lesion enhancement 5, 10, and 20 minutes after contrast administration was quantified as relative enhancement ratio (RER). With either gadolinium-based contrast agent, damaged myocardium had higher signal intensity than normal remote myocardium (RER > 4) on delayed-enhancement MR images, and the blood RER declined over time after contrast administration. The blood RER was not significantly higher for gadobenate dimeglumine than for gadopentetate dimeglumine at 5 and 10 minutes. Nevertheless, there was a larger reduction in blood RER for gadobenate dimeglumine than for gadopentetate dimeglumine between 5 and 10 minutes and between 10 and 20 minutes. The volumes of enhancement were similar for gadobenate dimeglumine (13.6 ± 8.8 cm(3)) and gadopentetate dimeglumine (13.5 ± 8.9 cm(3)) (p = 0.98). The mean difference in Bland-Altman analysis for delayed-enhancement volume between the agents was 0.1 cm(3). Qualitatively and quantitatively, delayed-enhancement MR images of ischemic myocardium obtained with 0.1 mmol/kg gadobenate dimeglumine are comparable to those obtained with 0.2 mmol/kg gadopentetate dimeglumine 5, 10, and 20 minutes after contrast administration.


Factors associated with severity of road traffic injuries, Thika, Kenya.
Road traffic injuries continue to exert a huge burden on the health care system in Kenya. Few studies on the severity of road traffic injuries have been conducted in Kenya. We carried out a cross-sectional study to determine factors associated with severity of road traffic injuries in a public hospital in Thika district, Kenya. Road crash victims attending the Thika district hospital, a 265-bed public hospital, emergency room were recruited consecutively between 10th August 2009 and 15th November 2009. Epidemiologic and clinical information was collected from medical charts and through interview with the victims or surrogates using a semi-structured questionnaire. Injuries were graded as severe or non-severe based on the Injury Severity Score (ISS). Independent factors associated with injury severity were assessed using multivariate logistic regression. The mean age of participants was 32.4 years, three quarters were between 20-49 years-old and 73% (219) were male. Nineteen percent (56/300) of the victims had severe injury. Five percent (15) had head injury while 38% (115) had fractures. Vulnerable road users (pedestrians and two-wheel users) comprised 33% (99/300) of the victims. Vulnerable road users (OR=2.0, 95%CI=1.0-3.9), road crashes in rainy weather (OR=2.9, 95%CI=1.3-6.5) and night time crashes (OR=2.0, 95%CI=-1.1-3.9) were independent risk factors for sustaining severe injury. Severe injury was associated with vulnerable road users, rainy weather and night time crashes. Interventions and measures such as use of reflective jackets and helmets by two wheel users and enhanced road visibility could help reduce the severity of road traffic injuries.


Tumour mutational burden: primary versus metastatic tissue creates systematic bias.
Tumour mutational burden (TMB) has emerged as a reproducible biomarker to predict immunotherapy response across multiple cancer types. However, a key aspect of TMB measurement that is often overlooked is the source of tissue sample used, which creates a potential for systematic bias. The predominant source is either primary or metastatic tumour tissue. Primary tumours are more heterogeneous and reflect a longer period of tumour evolution, whereas metastases tend to have a more monoclonal structure and potentially different TMB scores. Studies to date measuring TMB have used a heterogeneous set of primary and metastatic tissues, which may explain some of the variability in predictive TMB values across studies. This paper presents data to show that there is a systematic difference whereby metastatic TMB is biased towards higher values than primary TMB (36% higher, paired Wilcoxon, P = 0.0008). However, effectiveness in predicting overall survival during immune checkpoint inhibitor therapy was found to be equivalent between primary and metastatic TMB. We highlight that lower TMB in primary tissue may be important in cases with borderline primary TMB, where assaying metastatic TMB may lead to a different treatment stratification result. As TMB progresses towards clinical implementation, particularly in classically non-immunogenic tumour types, it is important to have better curated trials with either the source of tissue annotated or a prospective study assessing concordance between paired primary and metastatic tissue.


Evolution of double-stranded DNA viruses of eukaryotes: from bacteriophages to transposons to giant viruses.
Diverse eukaryotes including animals and protists are hosts to a broad variety of viruses with double-stranded (ds) DNA genomes, from the largest known viruses, such as pandoraviruses and mimiviruses, to tiny polyomaviruses. Recent comparative genomic analyses have revealed many evolutionary connections between dsDNA viruses of eukaryotes, bacteriophages, transposable elements, and linear DNA plasmids. These findings provide an evolutionary scenario that derives several major groups of eukaryotic dsDNA viruses, including the proposed order "Megavirales," adenoviruses, and virophages from a group of large virus-like transposons known as Polintons (Mavericks). The Polintons have been recently shown to encode two capsid proteins, suggesting that these elements lead a dual lifestyle with both a transposon and a viral phase and should perhaps more appropriately be named polintoviruses. Here, we describe the recently identified evolutionary relationships between bacteriophages of the family Tectiviridae, polintoviruses, adenoviruses, virophages, large and giant DNA viruses of eukaryotes of the proposed order "Megavirales," and linear mitochondrial and cytoplasmic plasmids. We outline an evolutionary scenario under which the polintoviruses were the first group of eukaryotic dsDNA viruses that evolved from bacteriophages and became the ancestors of most large DNA viruses of eukaryotes and a variety of other selfish elements. Distinct lines of origin are detectable only for herpesviruses (from a different bacteriophage root) and polyoma/papillomaviruses (from single-stranded DNA viruses and ultimately from plasmids). Phylogenomic analysis of giant viruses provides compelling evidence of their independent origins from smaller members of the putative order "Megavirales," refuting the speculations on the evolution of these viruses from an extinct fourth domain of cellular life.


Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study.
Allergic symptoms are generally caused by exposure to substances to which people have become sensitized. Associated with this is an 'unbalanced' Th1/Th2 immune response with T cell responses skewed towards the production of Th2 cytokines, IL-4, 5, and 13 and high levels of IgE antibodies. Current immune modulating therapies require the use of allergens, carrying the risk to induce potentially severe allergic reactions. Goal of the present study was to assess the safety and efficacy of an allergen-free immune modulator in patients suffering from perennial allergy. In order to be protected from immediate degradation upon injection, a toll-like receptor 9 (TLR9) agonist was packaged into virus-like particles. These nanoparticles loaded with TLR9 ligands (CYT003-QbG10) were injected six times, at weekly intervals, into patients with house dust mite allergy in an attempt to ameliorate allergic symptoms by modifying the immune response towards allergens. Two different doses were compared against placebo in this double-blind, randomized phase IIb study (n=299). Public trial registry: http://clinicaltrials.gov (NCT00800332). The treatment was safe and generally well tolerated. Rhinoconjunctivitis symptoms were significantly lower in patients treated with high dose of CYT003-QbG10 as compared with placebo (scores 0.31 vs. 0.52, P=0.04) based on a standardized average combined symptom and medication score. Furthermore, patients in the high dose group reported a significantly better quality of life score post-treatment than patients on placebo (scores 0.71 vs. 1.21, P=0.02). The conjunctival provocation test revealed a median 10-fold increase in allergen tolerance in the high dose group while in the placebo group it remained unchanged. Treatment with high-dose CYT003-QbG10 improved disease symptoms and reduced medication use in allergic individuals thus providing first evidence for a new potential immunotherapeutic.


False Memories for Fake News During Ireland's Abortion Referendum.
The current study examined false memories in the week preceding the 2018 Irish abortion referendum. Participants (N = 3,140) viewed six news stories concerning campaign events-two fabricated and four authentic. Almost half of the sample reported a false memory for at least one fabricated event, with more than one third of participants reporting a specific memory of the event. "Yes" voters (those in favor of legalizing abortion) were more likely than "no" voters to "remember" a fabricated scandal regarding the campaign to vote "no," and "no" voters were more likely than "yes" voters to "remember" a fabricated scandal regarding the campaign to vote "yes." This difference was particularly strong for voters of low cognitive ability. A subsequent warning about possible misinformation slightly reduced rates of false memories but did not eliminate these effects. This study suggests that voters in a real-world political campaign are most susceptible to forming false memories for fake news that aligns with their beliefs, in particular if they have low cognitive ability.


Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment.
Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.


Complex-optical-field lidar system for range and vector velocity measurement.
A coherent lidar system based on the measurement of complex optical field is demonstrated for the first time. An electro-optic in-phase/quadrature (I/Q) modulator is used in the lidar transmitter to realize carrier-suppressed complex optical field modulation in which the positive and the negative optical sidebands can carry independent modulation waveforms. A fiber-optic 90° hybrid is used in the lidar receiver for coherent heterodyne detection and to recover the complex optical field. By loading a constant modulation frequency on the lower optical sideband and a wideband linear frequency chirp on the upper sideband, vector velocity and target distance can be measured independently. The wide modulation bandwidth of this lidar system also enabled unprecedented range resolution and the capability of measuring high velocity unambiguously.


Nurses who do not nurse: factors that predict non-nursing work in the U.S. registered nursing labor market.
Registered nurses (RNs) who work outside of nursing have seldom been examined. This aim of this study was to compare the 122,178 (4%) of RNs who are employed outside of nursing to those who work in nursing jobs in terms of sociodemographic, market, and political variables to determine if these groups are substantively different from one another. Using a logit regression model, wages were a significant predictor of working outside of nursing for unmarried nurses but not for married nurses. Married and unmarried male nurses were more likely to work outside of nursing. Baccalaureate education, children under age 6, higher family income, and years since graduation increased the odds of working outside of nursing for married nurses. Ultimately, identifying characteristics on which these groups differ may inform future policy directions that could target nurses who may leave nursing at a time when retention efforts might be effective to alter their trajectory away from the profession.


A prospective study of fasting plasma glucose and risk of stroke in asymptomatic men.
To examine the association between levels of fasting plasma glucose (FPG) and incidence of stroke outcomes in a large cohort of asymptomatic men. Participants were 43,933 men (mean ± SD age, 44.3 ± 9.9 years) who were free of known cardiovascular disease at baseline and whose FPG levels were assessed during a preventive medical examination at the Cooper Clinic, Dallas, TX, between January 7, 1971, and March 11, 2002. Patients with diagnosed diabetes mellitus (DM) or low FPG (<80 mg/dL [to convert to mmol/L, multiply by 0.0555]) were excluded. Fatal stroke was identified through the National Death Index, and nonfatal stroke was ascertained from mail-back surveys. A total of 595 stroke events (156 fatal and 456 nonfatal strokes; 17 men reported a nonfatal stroke before they died of stroke) occurred during 702,928 person-years of exposure. Age-adjusted fatal, nonfatal, and total stroke event rates per 10,000 person-years for normal FPG (80-109 mg/dL), impaired fasting glucose (110-125 mg/dL), and undiagnosed DM (≥ 126 mg/dL) were 2.1, 3.4, and 4.0 (P(trend)=.002); 10.3, 11.8, and 18.0 (P(trend)=.008); and 8.2, 9.6, and 12.4 (P(trend)=.008), respectively. After further adjusting for potential confounders, the direct association between FPG and fatal, nonfatal, or total stroke events remained significant (P(trend)=.02, .03, and .01, respectively). For FPG levels of 110 mg/dL or greater, each 10-unit increment of FPG was associated with a 6% higher risk of total stroke events (P=.05). Hyperglycemia (FPG, ≥ 110 mg/dL), even below the DM threshold (such as with impaired fasting glucose), was associated with a higher risk of fatal, nonfatal, or total stroke events in asymptomatic men.


Modulation of actin filament sliding by mutations of the SH2 cysteine in Dictyostelium myosin II.
The cysteine residue called SH2 in the skeletal myosin heavy chain is conserved among various species. Cys 678 in Dictyostelium myosin II is equivalent to SH2 in skeletal myosin. Using the Dictyostelium myosin II heavy chain gene, SH2 was mutated to Gly, Ala, Ser, or Thr. These mutant myosins were expressed in Dictyostelium myosin-null cells. To investigate how these mutations affect the motor functions of myosin, we examined the phenotypes of the transformed cells. We also purified the mutant myosins, and characterized them by measuring the actin-activated MgATPase activity, sliding velocity of actin filaments and force level. All of these mutant myosins complemented the myosin-specific defects of the myosin-null cells. Consistent with these observed phenotypes, all of the purified mutant myosins retained similar actin-activated MgATPase activities and force levels to those of the wild-type myosin (WT). However, the sliding velocities of actin filaments were significantly different (WT > or = Ser > Ala >> Thr > Gly). In particular, the Gly and Thr mutants exhibited a striking decrease in velocity, while the Ser mutant exhibited velocity comparable to that of the wild-type myosin. Thus, mutations of SH2 resulted in uncoupling of ATP hydrolysis and the sliding.


Preschool ADHD Diagnosis and Stimulant Use Before and After the 2011 AAP Practice Guideline.
To evaluate the change in the diagnosis of attention-deficit/hyperactivity disorder (ADHD) and prescribing of stimulants to children 4 to 5 years old after release of the 2011 American Academy of Pediatrics guideline. Electronic health record data were extracted from 63 primary care practices. We included preventive visits from children 48 to 72 months old receiving care from January 2008 to July 2014. We compared rates of ADHD diagnosis and stimulant prescribing before and after guideline release using logistic regression with a spline and clustering by practice. Patterns of change (increase, decrease, no change) were described for each practice. Among 87 067 children with 118 957 visits before the guideline and 56 814 with 92 601 visits after the guideline, children had an ADHD diagnosis at 0.7% (95% confidence interval [CI], 0.7% to 0.8%) of visits before and 0.9% (95% CI, 0.8% to 0.9%) after guideline release and had stimulant prescriptions at 0.4% (95% CI, 0.4% to 0.4%) of visits in both periods. A significantly increasing preguideline trend in ADHD diagnosis ended after guideline release. The rate of stimulant medication use remained constant before and after guideline release. Patterns of change from before to after the guideline varied significantly across practices. Release of the 2011 guideline that addressed ADHD in preschoolers was associated with the end of an increasing rate of diagnosis, and the rate of prescribing stimulants remained constant. These are reassuring results given that a standardized approach to diagnosis was recommended and stimulant treatment is not first-line therapy for this age group.


Aligning difficult airway guidelines with the anesthetic COVID-19 guidelines to develop a COVID-19 difficult airway strategy: a narrative review.
The coronavirus disease 2019 (COVID-19) pandemic is caused by a coronavirus that is transmitted primarily via aerosol, droplets or direct contact. This may place anesthetists at higher risk of infection due to their frequent involvement in aerosol-generating airway interventions. Many anesthethetic COVID-19 guidelines have emerged, whose underlying management principles include minimizing aerosol contamination and protecting healthcare workers. These guidelines originate from Australia and New Zealand, Canada, China, India, Italy, Korea, Singapore, the United States and the United Kingdom. Hospitalized COVID-19 patients may require airway interventions, and difficult tracheal intubation secondary to laryngeal edema has been reported. Pre-pandemic difficult airway guidelines include those from Canada, France, Germany, India, Japan, Scandinavia, the United States and the United Kingdom. These difficult airway guidelines require modifications in order to align with the principles of the anesthetic COVID-19 guidelines. In turn, most of the anesthetic COVID-19 guidelines do not, or only briefly, discuss an airway strategy after failed tracheal intubation. Our article identifies and compares pre-pandemic difficult airway guidelines with the recent anesthetic COVID-19 guidelines. We combine the principles from both sets of guidelines and explain the necessary modifications to the airway guidelines, to form a failed tracheal intubation airway strategy in the COVID-19 patient. Valuing, and a greater understanding of, these differences and modifications may lead to greater adherence to the new COVID-19 guidelines.


Diatoms response to salinity changes: investigations using single pulse and cross polarisation magic angle spinning 29Si NMR spectra.
Diatoms Thalassiosira pseudonana and Chaetoceros muelleri (Bacillariophyceae) were cultured at three different salinities (26, 36 and 46 practical salinity units (PSU)) and their silica content examined using natural abundance 29Si magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy. The samples were investigated using both single pulse (SP) and cross-polarisation (CP) MAS experiments. In addition, samples of T. pseudonana were examined using variable contact time CP MAS experiments allowing the dynamics (TSiH and T1rρH) of CP to be determined. Comparison of SP and CP results revealed a change to a less condensed silica state when diatoms were cultured at salinities away from optimal (36 PSU). Further, an increased amount of organic material (but not its composition) was determined to be present for such samples affecting CP experiments. The location of the organic material, on the diatom surface or within the frustule, was unable to be determined.


Basophil/mast cell precursors in human peripheral blood.
Semisolid (methylcellulose) hemopoietic cultures revealed the presence of histamine-containing granulocyte colonies derived from precursors (CFU-C) present in human peripheral blood. Light microscopy and histochemical studies of cells in individual histamine-containing colonies demonstrated homogeneous populations of metachromatic basophil/mast cells (BMC) at various stages of maturation. By inverted microscopy, pure BMC colonies were more often found to have the overall appearance of the previously described "eosinophil" (type II), rather than "neutrophil-macrophage" (type I), colony type. Histamine-positive colonies constituted 58% (50/86) of all (type I and type II) granulocyte colonies in repeated cultures from a patient with systemic mastocytosis (SM), and 19% (13/67) of colonies in cultures from 8 patients with chronic myeloid leukemia (CML); this was in contrast to 8% (12/153) of colonies in cultures from 4 patients with urticaria pigmentosa (UP) and 6 normal controls (p less than 0.0001). Calculated frequency of BMC CFU-C was approximately 1 per 2 X 10(6) in normal and 1 per 2 X 10(5) nucleated cells in SM peripheral blood. Taking colony size into account, histamine content per cell in histamine-positive type II colonies in SM cultures was 1.1 +/- 0.19 pg, compared to 0.29 +/- 0.08 pg in CML and less than or equal to 0.10 in normals and UP. Electron microscopy (EM) of individual colonies revealed electron-dense granules with ultrastructural features of BMC in histamine-positive, but not histamine-negative, colonies. Use of these methods may help to further clarify the nature of BMC precursors and the regulation of their proliferation in bone marrow disorders and allergic states.


Taxonomic study of aerobic thermophilic bacilli: descriptions of Geobacillus subterraneus gen. nov., sp. nov. and Geobacillus uzenensis sp. nov. from petroleum reservoirs and transfer of Bacillus stearothermophilus, Bacillus thermocatenulatus, Bacillus thermoleovorans, Bacillus kaustophilus, Bacillus thermodenitrificans to Geobacillus as the new combinations G. stearothermophilus, G. th.
Five hydrocarbon-oxidizing strains were isolated from formation waters of oilfields in Russia, Kazakhstan and China. These strains were moderately thermophilic, neutrophilic, motile, spore-forming rods, aerobic or facultatively anaerobic. The G+C content of their DNA ranged from 49.7 to 52.3 mol%. The major isoprenoid quinone was menaquinone-7; cellular fatty acid profiles consisted of significant amounts of iso-15:0, iso-16:0 and iso-17:0 fatty acids (61.7-86.8% of the total). Based on data from 16S rDNA analysis and DNA-DNA hybridization, the subsurface isolates could be divided into two groups, one of which consisted of strains UT and X and the other of which consisted of strains K, Sam and 34T. The new strains exhibited a close phylogenetic relationship to thermophilic bacilli of 'Group 5' of Ash et al. [Ash, C., Farrow, J. A. E., Wallbanks, S. & Collins, M. D. (1991). Lett Appl Microbiol 13, 202-206] and a set of corresponding signature positions of 16S rRNA. Comparative analysis of the 16S rDNA sequences and fatty acid compositions of the novel isolates and established species of thermophilic bacilli indicated that the subsurface strains represent two new species within a new genus, for which the names Geobacillus subterraneus gen. nov., sp. nov., and Geobacillus uzenensis sp. nov. are proposed. It is also proposed that Bacillus stearothermophilus, Bacillus thermoleovorans, Bacillus thermocatenulatus, Bacillus kaustophilus, Bacillus thermoglucosidasius and Bacillus thermodenitrificans be transferred to this new genus, with Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) as the type species.


Revascularization of the superior mesenteric artery alone for treatment of intestinal ischemia.
Complete revascularization is recommended by many authors for treatment of intestinal ischemia. The observation that postprandial intestinal hyperemia is limited to the superior mesenteric artery (SMA) has suggested to us that SMA revascularization alone should be adequate treatment. We preferentially manage intestinal ischemia with a single bypass graft to the SMA and herein update our results using this approach. Patients were identified from a prospectively established vascular surgical registry. Each patient was assessed for acute versus chronic intestinal ischemia, preoperative angiographic findings, operation used, perioperative morbidity and mortality, late symptomatic relief, cause of death, and life table-determined survival and graft patency. Graft patency was determined by follow-up angiography or duplex scanning. Fifty bypass grafts to the SMA alone were performed in 49 patients (31 women, 18 men; mean age, 62 years) for treatment of intestinal ischemia. In all patients additional splanchnic arteries were available for bypass grafting. Operative indications were acute symptoms in 21 patients, 14 of whom had bowel infarction; chronic symptoms in 26 patients; and prophylaxis in conjunction with infrarenal aortic surgery in 3 patients. Thirty-two grafts originated from the aorta or an iliac artery, and 18 originated from an aortic graft. There were 40 prosthetic and 10 autogenous conduits. Perioperative mortality was 3% in patients with chronic symptoms and 12% overall. All survivors were symptomatically improved. Mean follow-up was 44 months. Nine-year assisted primary graft patency was 79%, and 5-year patient survival was 61%. Two late deaths occurred in patients with recurrent intestinal ischemia resulting from graft occlusions. Bypass grafting to the SMA alone appears to be both an effective and durable procedure for treatment of intestinal ischemia. Our results appear equal to those reported for "complete" revascularization for intestinal ischemia. When the SMA is a suitable recipient vessel, multiple bypass grafts to other splanchnic vessels are unnecessary in the treatment of intestinal ischemia.


Exploiting sparsity in time-of-flight range acquisition using a single time-resolved sensor.
Range acquisition systems such as light detection and ranging (LIDAR) and time-of-flight (TOF) cameras operate by measuring the time difference of arrival between a transmitted pulse and the scene reflection. We introduce the design of a range acquisition system for acquiring depth maps of piecewise-planar scenes with high spatial resolution using a single, omnidirectional, time-resolved photodetector and no scanning components. In our experiment, we reconstructed 64 × 64-pixel depth maps of scenes comprising two to four planar shapes using only 205 spatially-patterned, femtosecond illuminations of the scene. The reconstruction uses parametric signal modeling to recover a set of depths present in the scene. Then, a convex optimization that exploits sparsity of the Laplacian of the depth map of a typical scene determines correspondences between spatial positions and depths. In contrast with 2D laser scanning used in LIDAR systems and low-resolution 2D sensor arrays used in TOF cameras, our experiment demonstrates that it is possible to build a non-scanning range acquisition system with high spatial resolution using only a standard, low-cost photodetector and a spatial light modulator.


Identification of novel long non-coding RNAs in clear cell renal cell carcinoma.
Long non-coding RNAs (lncRNA) play an important role in carcinogenesis; knowledge on lncRNA expression in renal cell carcinoma is rudimental. As a basis for biomarker development, we aimed to explore the lncRNA expression profile in clear cell renal cell carcinoma (ccRCC) tissue. Microarray experiments were performed to determine the expression of 32,183 lncRNA transcripts belonging to 17,512 lncRNAs in 15 corresponding normal and malignant renal tissues. Validation was performed using quantitative real-time PCR in 55 ccRCC and 52 normal renal specimens. Computational analysis was performed to determine lncRNA-microRNA (MiRTarget2) and lncRNA-protein (catRAPID omics) interactions. We identified 1,308 dysregulated transcripts (expression change >2-fold; upregulated: 568, downregulated: 740) in ccRCC tissue. Among these, aberrant expression was validated using PCR: lnc-BMP2-2 (mean expression change: 37-fold), lnc-CPN2-1 (13-fold), lnc-FZD1-2 (9-fold), lnc-ITPR2-3 (15-fold), lnc-SLC30A4-1 (15-fold), and lnc-SPAM1-6 (10-fold) were highly overexpressed in ccRCC, whereas lnc-ACACA-1 (135-fold), lnc-FOXG1-2 (19-fold), lnc-LCP2-2 (2-fold), lnc-RP3-368B9 (19-fold), and lnc-TTC34-3 (314-fold) were downregulated. There was no correlation between lncRNA expression with clinical-pathological parameters. Computational analyses revealed that these lncRNAs are involved in RNA-protein networks related to splicing, binding, transport, localization, and processing of RNA. Small interfering RNA (siRNA)-mediated knockdown of lnc-BMP2-2 and lnc-CPN2-1 did not influence cell proliferation. We identified many novel lncRNA transcripts dysregulated in ccRCC which may be useful for novel diagnostic biomarkers.


Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes.
The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)-mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass.


EvoMD: an algorithm for evolutionary molecular design.
Traditionally, Computer-Aided Molecular Design (CAMD) uses heuristic search and mathematical programming to tackle the molecular design problem. But these techniques do not handle large and nonlinear search space very well. To overcome these drawbacks, graph-based evolutionary algorithms (EAs) have been proposed to evolve molecular design by mimicking chemical reactions on the exchange of chemical bonds and components between molecules. For these EAs to perform their tasks, known molecular components, which can serve as building blocks for the molecules to be designed, and known chemical rules, which govern chemical combination between different components, have to be introduced before the evolutionary process can take place. To automate molecular design without these constraints, this paper proposes an EA called Evolutionary Algorithm for Molecular Design (EvoMD). EvoMD encodes molecular designs in graphs. It uses a novel crossover operator which does not require known chemistry rules known in advanced and it uses a set of novel mutation operators. EvoMD uses atomics-based and fragment-based approaches to handle different size of molecule, and the value of the fitness function it uses is made to depend on the property descriptors of the design encoded in a molecular graph. It has been tested with different data sets and has been shown to be very promising.


Efficient charge separation in TiO2 films sensitized with ruthenium(II)-polypyridyl complexes: hole stabilization by ligand-localized charge-transfer states.
We have studied the interfacial electron-transfer dynamics on TiO(2) film sensitized with synthesized ruthenium(II)-polypyridyl complexes--[Ru(II)(bpy)(2)(L(1))] (1) and [Ru(II)(bpy)(L(1))(L(2))] (2), in which bpy=2,2'-bipyridyl, L(1)=4-[2-(4'-methyl-2,2'-bipyridinyl-4-yl)vinyl]benzene-1,2-diol, and L(2)=4-(N,N-dimethylaminophenyl)-2,2'-bipyridine-by using femtosecond transient absorption spectroscopy. The presence of electron-donor L(2) and electron-acceptor L(1) ligands in complex 2 introduces lower energetic ligand-to-ligand charge-transfer (LLCT) excited states in addition to metal-to-ligand (ML) CT manifolds of complex 2. On photoexcitation, a pulse-width-limited (<100 fs) electron injection from populating LLCT and MLCT states are observed on account of strong catecholate binding on the TiO(2) surface. The hole is transferred directly or stepwise to the electron-donor ligand (L(2)) as a consequence of electron injection from LLCT and MLCT states, respectively. This results an increased spatial charge separation between the hole residing at the electron-donor (L(2)) ligand and the electron injected in TiO(2) nanoparticles (NPs). Thus, we observed a significant slow back-electron-transfer (BET) process in the 2/TiO(2) system relative to the 1/TiO(2) system. Our results suggest that Ru(II) -polypyridyl complexes comprising LLCT states can be a better photosensitizer for improved electron injection yield and slow BET processes in comparison with Ru(II)-polypyridyl complexes comprising MLCT states only.