Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry.
The purpose of this study was to describe the prevalence and severity of coronary artery disease (CAD) in relation to prognosis in symptomatic patients without coronary artery calcification (CAC) undergoing coronary computed tomography angiography (CCTA). The frequency and clinical relevance of CAD in patients without CAC are unclear. We identified 10,037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as <50%, ≥50%, and ≥70% stenosis. All-cause mortality and the composite endpoint of mortality, myocardial infarction, or late coronary revascularization (≥90 days after CCTA) were assessed. Mean age was 57 years, 56% were men, and 51% had a CAC score of 0. Among patients with a CAC score of 0, 84% had no CAD, 13% had nonobstructive stenosis, and 3.5% had ≥50% stenosis (1.4% had ≥70% stenosis) on CCTA. A CAC score >0 had a sensitivity, specificity, and negative and positive predictive values for stenosis ≥50% of 89%, 59%, 96%, and 29%, respectively. During a median of 2.1 years, there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8,907 patients with follow-up for the composite endpoint, 3.9% with a CAC score of 0 and ≥50% stenosis experienced an event (hazard ratio: 5.7; 95% confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8% of patients with a CAC score of 0 and no obstructive CAD. Receiver-operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84). In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.


Controlled Release of Growth Factors from Multilayered Fibrous Scaffold for Functional Recoveries in Crushed Sciatic Nerve.
In this study, we designed and fabricated a multilayered fibrous scaffold capable of the controlled release of multiple growth factors for sciatic nerve regeneration in rats. The scaffold consists of three layers prepared by sequential electrospinning, where the first layer is fabricated using polycaprolactone (PCL)-aligned electrospun nanofibers for the attachment and differentiation of cells toward the direction of the sciatic nerve. The second and third layers are fabricated using poly(lactic-co-glycolic acid) 6535 (PLGA 6535) and 8515 (PLGA 8515), respectively. The resultant three nanofiber layers were stacked and fixed by incorporating hydrogel micropatterns at both ends of nanofiber scaffold, which also facilitated the surgical handling of the multilayered scaffolds. The PLGA layers acted as reservoirs to release growth factors neurotrophin (NT-3), brain-derived neurotrophic factor (BDNF), and platelet-derived growth factor (PDGF). The different biodegradation rate of each PLGA layer enabled the controlled release of multiple growth factors such as NT-3, BDNF, and PDGF with different patterns. In a rat model, the injured nerve was rolled up with the multilayered scaffold loading growth factors, and behavior tests were performed five weeks after surgery. Sciatic functional index (SFI) and mechanical allodynia analysis revealed that the fast release of NT-3 and BDNF from PLGA 6535 and subsequent slow release of PDGF from PLGA 8515 proved to be the greatest aid to neural tissue regeneration. In addition to the biochemical cues from growth factors, the aligned PCL layer that directly contacts the injured nerve could provide topographical stimulation, offering practical assistance to new tissue and cells for directional growth parallel to the sciatic nerve. This study demonstrated that our multilayered scaffold performs a function that can be used to promote locomotor activity and enhance nerve regeneration in combination with align-patterned topography and the controlled release of growth factors.


Plastic bending of sapphire fibers for infrared sensing and power-delivery applications.
Sapphire fibers with diameters of 325-850 microm were plastically bent by CO(2) laser beams with typical bending radii as small as 2.8 mm. The additional optical loss caused by a single bend was less than 0.1 dB (at 900 nm), the damage threshold of the bent fibers was higher than 150 MW/cm(2) for Nd:YAG laser pulses, and the high mechanical strength of the bending area was also proved. Several successful applications of bent sapphire fibers have shown that plastically bent sapphire fibers are promising for use in IR sensing and power-delivery applications.


Activation of peroxisome proliferator-activated receptor δ inhibits angiotensin II-induced activation of matrix metalloproteinase-2 in vascular smooth muscle cells.
We investigated the role of peroxisome proliferator-activated receptor (PPAR) δ on angiotensin (Ang) II-induced activation of matrix metalloproteinase (MMP)-2 in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, attenuated Ang II-induced activation of MMP-2 in a concentration-dependent manner. GW501516 also inhibited the generation of reactive oxygen species in VSMCs treated with Ang II. A marked increase in the mRNA levels of tissue inhibitor of metalloproteinase (TIMP)-2 and -3, endogenous antagonists of MMPs, was also observed in GW501516-treated VSMCs. These effects were markedly reduced in the presence of siRNAs against PPARδ, indicating that the effects of GW501516 are PPARδ dependent. Among the protein kinases inhibited by GW501516, suppression of phosphatidylinositol 3-kinase/Akt signaling was shown to have the greatest effect on activation of MMP-2 in VSMCs treated with Ang II. Concomitantly, GW501516-mediated inhibition of MMP-2 activation in VSMCs treated with Ang II was associated with the suppression of cell migration to levels approaching those in cells not exposed to Ang II. Thus, activation of PPARδ confers resistance to Ang II-induced degradation of the extracellular matrix by upregulating expression of its endogenous inhibitor TIMP and thereby modulating cellular responses to Ang II in vascular cells.


Protocol for a systematic review of screening tools for fear of recurrent illness in common life-threatening diseases.
A myocardial infarction (MI) ('heart attack') can be intensely stressful, and the impact of this event can leave patients with clinically significant post-MI stress symptoms. Untreated stress can make heart disease worse. Few tools are available that screen for specific thoughts or beliefs that can trigger post-MI stress responses. In other life-threatening illnesses, fear of recurrence (FoR) of illness has been identified as a key stressor, and screening tools have been developed to identify this. The aim of this review is to identify FoR screening tools used in other common life-threatening diseases that report on the development of the tool, to assess if there are any that can be adapted for use in MI survivors so that those with high levels of FoR can be identified and helped. The review will evaluate full FoR screening tools and methods of measurement used in common life-threatening disease clinical populations. The Campbell and Cochrane Libraries, Cumulative Index of Nursing and Allied Health Literature (CINAHL), PsycINFO, MEDLINE, Embase, Applied Social Sciences Index and Abstracts (ASSIA), Published International Literature on Traumatic Stress (PILOTS), Social Services Abstracts, Sociological Abstracts, Web of Knowledge, Health and Psychosocial Instruments and SCOPUS databases will be searched for relevant studies published from database inception. Reference lists and published reviews/meta-analyses will also be searched. All titles and abstracts will be screened and relevant full-text versions retrieved by two reviewers, who will then extract all the data. Each will independently review all data extracted by the other. Selected studies will also be assessed by two independent researchers using the COnsensus-based standards for the Selection of health status measurement INstruments (COSMIN) checklist and other quality criteria. This will be done to evaluate the degree to which their measurement properties meet the standards for good methodological quality. Disagreement will be resolved through consensus. Untreated post-MI stress has a considerable psychological and physical impact on MI survivors. Therefore, there is a critical need to develop a screening tool to identify fear of recurrent MI so that those affected can be identified and directed to appropriate support interventions. This proposed research will enable a tool to be developed and adapted for use in the MI survivor patient population. CRD42014010500.


Disseminating best practice through teaching.
A nurse may be invited to deliver teaching sessions to students at a local university, especially if he or she has a reputation as a practice innovator. These invitations are an opportunity for the nurse to disseminate practice wisdom to a wider audience. Planning the session so that it is educational, stimulating and represents the nurse's experience and expertise is crucial. While leading such a session may seem daunting, there are several strategies that can increase the chance of success, and these are discussed in this article.


Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction.
Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking. To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden. Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010. In-hospital treatment with fondaparinux or LMWH during the hospital stay. In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization. In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups. In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward.


Impact of local attenuation approximations when estimating correlation length from backscattered ultrasound echoes.
Estimating the characteristic correlation length of tissue microstructure from the backscattered power spectrum could improve the diagnostic capability of medical ultrasound. Previously, size estimates were obtained after compensating for source focusing, the frequency-dependent attenuation along the propagation path (total attenuation), and the frequency-dependent attenuation in the scattering region (local attenuation). In this study, the impact of approximations of the local attenuation on the scatterer size estimate was determined using computer simulations and theoretical analysis. The simulations used Gaussian impedance distributions with an effective radius of 25 microm randomly positioned in a homogeneous half-space sonified by a spherically focused source (f/1 to f/4). The approximations of the local attenuation that were assessed neglected local attenuation (i.e., assume 0 dB/cm-MHz) neglected frequency dependence of the local attenuation, and assumed a finite frequency dependence (i.e., 0.5 dB/cm-MHz) independent of the true attenuation of the medium. Errors in the scatterer size estimate due to the local attenuation approximations increased with increasing window length, increasing true local attenuation and increasing f number. The most robust estimates were obtained when the local attenuation was approximated by a tissue-independent attenuation value that was greater than 70% of the largest attenuation expected in the tissue region of interest.


Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology.
This study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)]. The study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison. The vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups. At the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology.


A Global Reassessment of Solitary-Sociable Dolphins.
Dolphins are typically regarded as highly social animals. However, some individuals live apart from their own species and may come to socialize with people through a recognized series of stages which are presented and expanded on in this paper. The term "solitary-sociable dolphins" has been used to describe these animals and such individuals have been identified from several different species and reported in many parts of the world. In many instances, the interactions with people that may follow their original isolation, and which typically become more intense over time, have created situations where the welfare of the animal has been compromised by disturbance, injury, the feeding of inappropriate items and aggressive human behavior. Several solitary-sociable dolphins have also been deliberately injured and killed by humans. People who interact with these dolphins may also put themselves at risk of injury. This paper reports on recent cases drawing on published and unpublished sources. Since 2008, 32 solitary dolphins have been recorded including 27 bottlenose dolphins (25 Tursiops truncatus and two Tursiops aduncus), two striped dolphins and three common dolphins. Four solitary belugas have also been recorded. There are some ten solitary dolphins and one beluga known at the present time. Laws and guidelines currently in place to protect solitary-sociable dolphins need to be strengthened and interactions with people should be avoided or, at the least, carefully managed to protect both the dolphin and the humans involved in the interaction. Terms, such as disturbance and harassment which are included in laws need to be clearly defined. Additionally, management plans for solitary-sociable dolphins need to be developed and adapted on a case by case basis taking into account the individual dolphin's sex, age, personality, stage of sociability and home range. It is also important that government officials and local stakeholders work together to implement guidelines which set out how the public can observe or interact with the dolphin safely.


Discovery of Paenibacillus larvae ERIC V: Phenotypic and genomic comparison to genotypes ERIC I-IV reveal different inventories of virulence factors which correlate with epidemiological prevalences of American Foulbrood.
Paenibacillus larvae is the etiological agent of American Foulbrood (AFB), a highly contagious brood disease of honey bees (Apis mellifera). AFB requires mandatory reporting to the veterinary authority in many countries and until now four genotypes, P. larvae ERIC I-IV, have been identified. We isolated a new genotype, ERIC V, from a Spanish honey sample. After a detailed phenotypic comparison with the reference strains of the ERIC I-IV genotypes, including spore morphology, non-ribosomal peptide (NRP) profiling, and in vivo infections of A. mellifera larvae, we established a genomic DNA Macrorestriction Fragment Pattern Analysis (MRFPA) scheme for future epidemiologic discrimination. Whole genome comparison of the reference strains and the new ERIC V genotype (DSM 106052) revealed that the respective virulence gene inventories of the five genotypes corresponded with the time needed to kill 100 % of the infected bee larvae (LT100) in in vivo infection assays. The rarely isolated P. larvae genotypes ERIC II I-V with a fast-killing phenotype (LT100 3 days) harbor genes with high homology to virulence factors of other insect pathogens. These virulence genes are absent in the epidemiologically prevalent genotypes ERIC I (LT100 12 days) and ERIC II (LT100 7 days), which exhibit slower killing phenotypes. Since killing-retardation is known to reduce the success of hygienic cleaning by nurse bees, the identified absence of virulence factors might explain the epidemiological prevalences of ERIC genotypes. The discovery of the P. larvae ERIC V isolate suggests that more unknown ERIC genotypes exist in bee colonies. Since inactivation or loss of a few genes can transform a fast-killing phenotype into a more dangerous slow-killing phenotype, these rarely isolated genotypes may represent a hidden reservoir for future AFB outbreaks.


Outcome of pregnancies in patients with complex pulmonary atresia.
To evaluate the outcome of pregnancies in patients with complex pulmonary atresia, comparing those with and without previous radical surgical repair. A retrospective study of all pregnancies in women with complex pulmonary atresia registered on the Grown-up Congenital Heart Unit database between 1977 and 1994. Referral centre for adolescents and adults with congenital heart disease. Forty one pregnancies occurred in 15 patients. They were divided into two groups; group I, 26 pregnancies in nine patients before radical repair (cyanotic); group II, 15 pregnancies in seven women after radical surgical repair. In group I there were three terminations, 13 miscarriages, eight healthy children, and two neonatal deaths. Five children were born prematurely and all had low birthweights. In group II there were two miscarriages, 11 normal children, and two children with congenital heart disease. None was premature and all had normal birthweights. There were major complications in both groups: in group I there were two thromboembolic complications and one episode of heart failure; in group II there was one pulmonary embolism and one arrhythmic complication, five pregnancies in three patients were complicated by left ventricular failure that was persistent in one case and progressive in another, leading to death 13 months after delivery. Patients with complex pulmonary atresia, with or without surgical repair, who have no or mild symptoms, can have successful pregnancies. Surgical repair decreases fetal complications significantly. In both groups thrombotic disorders and heart failure must be prevented. Patients with residual systemic-pulmonary collaterals after surgical repair are particularly at risk of left ventricular failure.


Profile of the Health and Nutritional Status of Older Adults in Mexico. 2012 National Health and Nutrition Survey.
The health and nutritional conditions of older adults in Mexico are heterogeneous. The prevalence of chronic noncommunicable diseases is elevated with disparities in functionality and socioeconomic inequities. To obtain updated information of the health and nutritional profile of older adults in Mexico in a national representative sample. Information was obtained from 6,687 60 years and older adults from the 2012 National Health and Nutrition Survey (ENSANUT 2012). An index defining the status of «healthy adult» was constructed taking into account the variables of independence in performing activities of daily living (ADL), based on the development by Katz, instrumental ADL, no chronic diseases, nonsmoker and no active use of alcohol. Tables of frequencies and proportions were constructed and expanded to describe the general characteristics and nutritional status of the adult Mexican population. A logistic regression model was used to study changes in the probability of being classified as a healthy adult with respect to different variables of interest. Probabilities using the delta method were estimated to establish 95% confidence intervals. In this study 12.2% of the older adults, were classified as healthy. The logistic regression model adjusted for the variables included in the study shows that the interaction of age and gender is significant (P = 0.068), where the probability of healthy adult status decreases in women with ageing and remains stable for men. Also, living in the southern region of the country significantly decreases the probability of healthy adult status (P = 0.001). Gender of the older adult was not significant. In Mexico, the health conditions of older adults are deficient. Public policies need to be generated that are directed at this population group and will translate into self-care actions in the early stages of life so as to guarantee a healthy future.


Stochastic rounding and reduced-precision fixed-point arithmetic for solving neural ordinary differential equations.
Although double-precision floating-point arithmetic currently dominates high-performance computing, there is increasing interest in smaller and simpler arithmetic types. The main reasons are potential improvements in energy efficiency and memory footprint and bandwidth. However, simply switching to lower-precision types typically results in increased numerical errors. We investigate approaches to improving the accuracy of reduced-precision fixed-point arithmetic types, using examples in an important domain for numerical computation in neuroscience: the solution of ordinary differential equations (ODEs). The Izhikevich neuron model is used to demonstrate that rounding has an important role in producing accurate spike timings from explicit ODE solution algorithms. In particular, fixed-point arithmetic with stochastic rounding consistently results in smaller errors compared to single-precision floating-point and fixed-point arithmetic with round-to-nearest across a range of neuron behaviours and ODE solvers. A computationally much cheaper alternative is also investigated, inspired by the concept of dither that is a widely understood mechanism for providing resolution below the least significant bit in digital signal processing. These results will have implications for the solution of ODEs in other subject areas, and should also be directly relevant to the huge range of practical problems that are represented by partial differential equations. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.


Comparison of left ventricular mass in normotensive type 2 diabetes mellitus patients with that in the nondiabetic population.
Cardiovascular disease is increased in individuals with type 1 or type 2 diabetes mellitus (DM). Left ventricular hypertrophy (LVH), which is an ominous prognostic sign and an independent risk factor for cardiac events, is often present in type 2 DM patients. The aim of our cross-sectional study was to evaluate the prevalence of LVH, and risk factors for its development, in normotensive type 2 diabetic patients without antihypertensive medication. The objectives of the study were to find out the prevalence of high left ventricular mass (LVM) in normotensive type 2 diabetic patients and compare it with nondiabetics and to uncover the risk factors for the development of high LVM in normotensive type 2 diabetic patients. A total of 130 age- and sex-matched subjects were selected (65 cases, diabetic normotensive, and 65 controls, nondiabetic normotensive) and baseline data were collected. LVM and left ventricular mass index (LVMI) were calculated using echocardigraphic parameters and body surface area. LVMI was significantly higher in patients with type 2 DM compared with age-, sex-matched healthy population (104.9 ± 21 vs. 78.5 ± 22.7 g/m(2), respectively; P < 0.05). BMI, HbA1c, and duration of diabetes were significantly associated with LVH whereas sexes, age, PPBS, were not.


Health effects of vitamin D.
Increasing data suggest that many or most adults in the United States and Europe would benefit from vitamin D supplements. This review summarizes the benefits of vitamin D with the strongest evidence today from randomized controlled trials for fall and fracture prevention. Beyond fall and fracture prevention, vitamin D may also reduce overall morbidity by multiple mechanisms. Prospective epidemiological studies supported by strong mechanistic evidence suggest a reduction of cardiovascular disease (incident hypertension and cardiovascular mortality) and colorectal cancer, extending to weaker evidence on immune-modulatory and anti-inflammatory benefits of vitamin D.


Distribution and Schistosoma mansoni infection of Biomphalaria glabrata in different habitats in a rural area in the Jequitinhonha Valley, Minas Gerais, Brazil: environmental and epidemiological aspects.
This paper examines the distribution and infection of Biomphalaria glabrata with Schistosoma mansoni in all aquatic snail habitats in a rural area in the state of Minas Gerais, Brazil, in relation to physico/biotic and behavioral factors. Snail and environmental surveys were carried out semi-annually between July 2001 and November 2002 at 106 sites. Collected snails were examined in the laboratory for infection. B. glabrata densities were highest in overflow ponds, irrigation ponds, springs, canals and wells, and lowest in fishponds and water tanks. Snail densities were higher during the hot, rainy season except for streams and canals and were statistically associated with the presence of fish, pollution, and vegetation density. Tilapia fish and an unidentified Diptera larva were found to be predators of B. glabrata but ducks were not. Twenty-four of the 25 infected snails were collected in 2001(1.4% infection rate) and only one in 2002, after mass chemotherapy. The occurrence of B. glabrata in all 11 snail habitats both at and away from water contact sites studied indicates widespread risk of human infection in the study area. In spite of the strong association between B. glabrata and tilapia in fishponds we do not recommend its use in schistosomiasis control for ecological reasons and its relative inefficiency in streams and dams.


Lung cancer: a new frontier for microbiome research and clinical translation.
The lung microbiome has been shown to reflect a range of pulmonary diseases-for example: asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Studies have now begun to show microbiological changes in the lung that correlate with lung cancer (LC) which could provide new insights into lung carcinogenesis and new biomarkers for disease screening. Clinical studies have suggested that infections with tuberculosis or pneumonia increased the risk of LC possibly through inflammatory or immunological changes. These have now been superseded by genomic-based microbiome sequencing studies based on bronchoalveolar lavage, sputum or saliva samples. Although some discrepancies exist, many have suggested changes in particular bacterial genera in LC samples particularly, Granulicatella, Streptococcus and Veillonella. Granulicatella is of particular interest, as it appeared to show LC stage-specific increases in abundance. We propose that these microbial community changes are likely to reflect biochemical changes in the LC lung, linked to an increase in anaerobic environmental niches and altered pyridoxal/polyamine/nitrogenous metabolism to which Granulicatella could be particularly responsive. These are clearly preliminary observations and many more expansive studies are required to develop our understanding of the LC microbiome.


Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy.
The association of a change in serum alkaline phosphatase (ALP) with overall survival OS in men with metastatic castration-resistant prostate cancer (CRPC) receiving chemotherapy is unknown. We evaluated the association of changes in ALP within 90 days with OS in men with CRPC and bone metastases treated with docetaxel or mitoxantrone in the TAX327 trial. Eligible patients included those with bony metastatic disease, baseline ALP ≥ 120 u/L (upper limit of normal) and ≥2 post-therapy measurements of ALP available. Survival was estimated using the Kaplan-Meier method and prognostic potential of change in ALP was evaluated using Cox proportional hazards regression. Surrogacy was calculated by the Likelihood Reduction Factor. 601 patients met the eligibility criteria. By day 90, 159 patients had ALP normalization (<120 u/L) and 442 patients did not normalize. Normalization of ALP remained prognostic for OS after adjusting for PSA decline ≥ 30% by day 90 (HR 0.79, 95% CI = 0.65-0.97, P = 0.022). Increase in ALP remained prognostic for OS when adjusting for PSA increase ≥ 50% by day 90 (HR 1.69, 95% CI = 1.33-2.14, P < 0.001). ALP changes did not meet criteria for surrogacy for OS. For men with CRPC, bone metastasis and high baseline ALP receiving docetaxel or mitoxantrone chemotherapy, normalization of ALP by day 90 was predictive of better survival independent of ≥30% PSA declines. An increase in ALP by day 90 was also predictive of poor survival independent of ≥50% PSA increase. Given the ready availability of ALP, the validation of our data is warranted.


Mitochondrial myopathy induces a starvation-like response.
Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.


Sex-dependent autosomal effects on clinical progression of Alzheimer's disease.
Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.


Tetrahymena H4 genes: structure, evolution and organization in macro- and micronuclei.
The ciliated protozoan Tetrahymena thermophila contains two types of H4 histone genes (H4-I and H4-II). Southern blotting and analysis of DNA from nullisomic strains indicate that H4-I and H4-II are on different chromosomes and that only H4-II is closely linked to an H3 gene. No DNA sequence rearrangements are observed for either of the H4 genes when the transcriptionally inert, germ line, micronucleus is compared to the transcriptionally active, somatic macronucleus. Comparison of the H4-I gene and its flanking sequences to H4 gene sequences of other organisms indicates that there are evolutionary constraints on coding nucleotides that are unrelated to their protein coding function and that these evolutionary pressures operate at the level of translation.


Brominated flame retardants in offices in Michigan, USA.
Brominated flame retardants (BFRs) are now ubiquitous contaminants with large reservoirs and high concentrations in buildings. Most of the information documenting BFR levels has been obtained in residences, and other environments that can lead to exposure have received relatively little attention, including offices that contain numerous BFR sources and where individuals spend considerable time. The aim of this study is to characterize BFR concentrations, potential emission sources, and migration pathways in office environments. We measure BFR levels in floor dust, indoor air, ventilation filter dust, and carpets in ten commercial and institutional buildings in Michigan, U.S.A. The median concentration of total BDEs in settled dust was 8754 ng g(-1), at the upper range of levels previously reported. Especially elevated levels were found in offices in buildings that contained known or likely BFR sources, e.g., computer servers. A trends analysis in a newly constructed building showed remarkable increases in concentrations of BFRs in settled dust and indoor air, and apparent steady-state levels were reached 5 to 8 months after building completion, a particularly striking finding given that the building was constructed and furnished several years after the voluntary phase-out of the penta- and octa-mixtures. Airborne particulate matter collected in a building's HVAC system filters contained PBDEs, including BDE-209, at levels exceeding the concentration of floor dust. In conjunction with estimates of building air flow rates, filter efficiency and other parameters, mass balance calculations for this building were used to estimate the emission rates and reservoirs of PBDEs. The widespread distribution of BFRs found in offices in both new and old buildings suggests the significance of workplace exposures, the need for controls to minimize human exposure, intra-building migration, and environmental releases of these chemicals, and the need for monitoring in new buildings to confirm the effectiveness of the PBDE phase-out.


Pulmonary complications in chronic liver disease.
The association of chronic liver disease with respiratory symptoms and hypoxia is well recognized. Over the last century, three pulmonary complications specific to chronic liver disease have been characterized: hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH). The development of portal hypertension is fundamental in the pathogenesis of each of these disorders. HPS is the most common condition, found in 5%-30% of cirrhosis patients, manifested by abnormal oxygenation due to the development of intrapulmonary vascular dilatations. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation (LT). POPH is characterized by development of pulmonary arterial hypertension in the setting of portal hypertension, and is present in 5%-10% of cirrhosis patients evaluated for LT. Screening for POPH in cirrhosis patients eligible for LT is critical since severe POPH is a relative contraindication for LT. Patients with moderate POPH, who respond adequately to medical therapy, may benefit from LT, although sufficient controlled data are lacking. HH is a transudative pleural effusion seen in 5%-10% of cirrhosis patients, in the absence of cardiopulmonary disease. Diagnosis of HH should prompt consideration for LT, which is the ultimate treatment for HH. Conservative management includes salt restriction and diuretics, with thoracentesis and transjugular intrahepatic portosystemic shunt (TIPS) as second-line therapeutic options.


Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries.
Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings. This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient's first year of treatment (11 rituximab sessions). Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p <0.0001). By country, relative reduction in time was 27-58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1-5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p <0.0001). By country, relative reduction was 53-91%. Absolute reduction in extrapolated chair time for the first year of treatment was 3.1-5.5 eight-hour days. Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units. ClinicalTrials.gov NCT01200758.


Impact of misclassification on measures of cardiovascular disease mortality in the Islamic Republic of Iran: a cross-sectional study.
To assess the extent and pattern of misclassification of death from non-specific diagnoses emanating from the Iranian death registration system, and to correct the data for health policy and planning. Detailed medical records for 1426 hospital deaths classified to seven ill-defined or vague causes of death were reviewed by trained physicians, who then completed standard death certificates. Underlying causes of death from the review were compared with the cause assigned in registration data. The probable underlying pattern of causes of death in the Islamic Republic of Iran is substantially different to that suggested by the death registration system. About 88% of 582 cases with non-specific diagnoses at ages 15-69 years were reassigned to various specific causes including ischaemic heart disease (33%), stroke (13%) and injuries (10%). A similar pattern of misclassification is apparent for 738 deaths at older ages (70 years and over), with 46% being reassigned to ischaemic heart disease and stroke. A significant proportion of deaths in the Iranian death registration system are being classified to cause groups of little relevance to epidemiological research or health policy. Reassignment of these deaths would increase the proportion of deaths from ischaemic heart disease and cerebrovascular diseases each by 32%, diabetes mellitus by 68% and chronic lower respiratory diseases by 73%. Substantial changes to procedures for diagnosing causes of death are urgently required if registration data are to effectively guide health policies and programmes in the Islamic Republic of Iran.


The effect of extremity vascular complications on the outcomes of cardiac support device recipients.
To assess the effect of extremity vascular complications (EVCs, including ischemia or vessel trauma) on the outcomes of patients receiving cardiac support devices (CSDs, including ventricular assist device [VAD] and extracorporeal membrane oxygenation [ECMO]). Institutional Review Board-approved, retrospective review of a prospectively maintained database of all temporary and permanent CSD recipients from 7/1/10 to 6/30/12. Patient demographics, procedural data, and outcomes were analyzed. The primary endpoint was all-cause mortality at 30-days post-CSD initiation. Of 208 patients who received CSDs, 31 (14.9%) experienced EVC: 13 (8.9%) of the 146 permanent VADs, 10 (26.3%) of the 38 temporary VADs, and 8 (33.3%) of the 24 ECMO patients. The 30-day mortality for CSD-EVC patients was not significantly higher than that of the CSD patients who did not experience EVC for permanent VAD (15.4% vs 4.5%; P = .15) and ECMO patients (50.0% vs 68.75%; P = 1.00), but was significantly higher for temporary VAD patients (80.0% vs 35.7%; P = .03). Within the CSD-EVC cohort, patients who received a temporary VAD had a significantly higher 30-day mortality and decision to withdraw care after EVC compared with those who received a permanent VAD (P = .01 and P < .01, respectively). Looking beyond the 30-day window, EVC was associated with higher mortality rates in the permanent VAD population (53.8% vs 25.6%; P = .025) but not the temporary VAD or ECMO groups. In temporary VAD recipients, EVCs result in higher 30-day mortality, more frequent withdrawal of care, and shortened survival time relative to the global temporary VAD group. EVC in permanent VAD recipients did not affect early (30-day) mortality rates, but strongly predicted a higher cumulative mortality risk for the 2-year study period. Overall ECMO mortality rates were high, and not significantly impacted by the occurrence of EVC. The nature of the EVC (cannulation site complication vs embolic injury) did not impact mortality. This data provides quality improvement targets for VAD programs.


Sexual functioning of Latino women seeking outpatient gynecologic care.
A sample of Latino women from an ambulatory obstetrics and gynecology (Ob/Gyn) clinic were queried about their sexual functioning using the Changes in Sexual Functioning Questionnaire (CSFQ-14). To assess the degree of self-reported sexual complaints in a sample of Latino women living in the United States; to assess if the prevalence of symptoms differs from one study of women living in Spain; and to determine if sexual complaints were associated with demographics, sexual/reproductive history, selected medications, or religious practices. CSFQ-14 scores and demographic variables. CSFQ-14 questionnaire in an out-patient, bilingual Ob/Gyn clinic in Central Virginia. Seventy-one native Spanish-speaking patients (59% born in Mexico) completed the U.S. Spanish version of the CSFQ-14 and a short questionnaire for potential covariates. The mean age was 28.7 years (range 17-60). Birth place was outside of the United States for 95.8% (N = 67). Eighty percent of participants had children and 96% reported being currently sexually active. Low sexual functioning, as defined by a total CSFQ score of < or = 41, was found in 26 (41.3%) participants. Taking medication for depression and/or anxiety was associated with lower sexual functioning (P = 0.03). Women who had children of any age living in the household were less likely to report low sexual functioning (P = 0.05; P = 0.01 when restricted to infants) than women without children living in the household. Thirteen of 68 women (19.1%) reported a history of physical and/or sexual abuse, but this was not associated with low sexual functioning. There was no association between self-reported religious affiliation or church attendance frequency and sexual complaints. Respondents in our sample had lower (i.e., worse sexual function) overall CSFQ scores compared with a sample of college students in Spain (P < 0.01), but higher (i.e., better sexual function) overall scores than workers in Spain (P < 0.04). On the subscales, our Latino population reported greater pleasure and less desire/interest than women who live in Spain. Self-reported rates of low sexual functioning were common in this cross section of Latino women. Medical treatment of depression and/or anxiety was associated with lower functioning. Direct inquiry about the sexual health of U.S. Latino women presenting for routine health care may assist in the identification of sexual difficulties in this population.


Forensic characterization and statistical considerations of the CaDNAP 13-STR panel in 1,184 domestic dogs from Germany, Austria, and Switzerland.
Crime scene samples originating from domestic dogs such as hair, blood, or saliva can be probative as possible transfer evidence in human crime and in dog attack cases. In the majority of such cases canine DNA identification using short tandem repeat (STR) analysis is the method of choice, which demands, among others, a systematic survey of allele frequency data in the relevant dog populations. A set of 13 highly polymorphic canine STR markers was used to analyze samples of 1,184 dogs (including 967 purebred dogs) from the so-called DACH countries (Germany, Austria, Switzerland). This CaDNAP 13-STR panel has previously been validated for canine identification in a forensic context. Here, we present robust estimates of allele frequencies, which are essential to assess the weight of the evidence by estimating the probability of a matching DNA profile within the dog population under question, e.g. in the form of a random match probability (RMP). The geographical provenance of the tested dogs showed a negligible influence on the observed genotype variation. Therefore, we combined the STR data from all three countries into a single dog population sample (DPS). In contrast, pronounced genetic differentiation between dog breeds was found by principal component analysis and sub-structure analysis with the STRUCTURE software. These findings entailed the need to account for the effects of DPS breed composition on allele frequency estimates. A possible strategy, which was favored here, relies on collecting a DPS that is guided by the breed composition of the relevant dog population. In total, dogs from 166 different breeds were included in our DPS, 64 of them including at least 5 individuals (n = 771 dogs). Sampling reflected the abundance of breeds in the DACH countries with the following being the most common ones: German Shepherds (population frequency: 14.3%), Dachshunds (5.9%), Labrador Retrievers (3.9%), and Golden Retrievers (3.2%). The pedigree listing of the purebred dogs in our DPS ranked German Shepherds (DPS frequency 8.5%) first, followed by Labrador Retrievers (3.9%), Golden Retrievers (3%), and Dachshunds (2.5%). RMP values based on overall allele frequencies and accounting for substructure using FST between breeds ranged between 10-13 and 10-14 and represent a conservative approach of RMP assessment.


Multiparametric Magnetic Resonance Imaging of the Prostate: Repeatability of Volume and Apparent Diffusion Coefficient Quantification.
The aim of this study was to evaluate the repeatability of a region of interest (ROI) volume and mean apparent diffusion coefficient (ADC) in standard-of-care 3 T multiparametric magnetic resonance imaging (mpMRI) of the prostate obtained with the use of endorectal coil. This prospective study was Health Insurance Portability and Accountability Act compliant, with institutional review board approval and written informed consent. Men with confirmed or suspected treatment-naive prostate cancer scheduled for mpMRI were offered a repeat mpMRI within 2 weeks. Regions of interest corresponding to the whole prostate gland, the entire peripheral zone (PZ), normal PZ, and suspected tumor ROI (tROI) on axial T2-weighted, dynamic contrast-enhanced subtract, and ADC images were annotated and assessed using Prostate Imaging Reporting and Data System (PI-RADS) v2. Repeatability of the ROI volume for each of the analyzed image types and mean ROI ADC was summarized with repeatability coefficient (RC) and RC%. A total of 189 subjects were approached to participate in the study. Of 40 patients that gave initial agreement, 15 men underwent 2 mpMRI examinations and completed the study. Peripheral zone tROIs were identified in 11 subjects. Tumor ROI volume was less than 0.5 mL in 8 of 11 subjects. PI-RADS categories were identical between baseline-repeat studies in 11/15 subjects and differed by 1 point in 4/15. Peripheral zone tROI volume RC (RC%) was 233 mm (71%) on axial T2-weighted, 422 mm (112%) on ADC, and 488 mm (119%) on dynamic contrast-enhanced subtract. Apparent diffusion coefficient ROI mean RC (RC%) were 447 × 10 mm/s (42%) in PZ tROI and 471 × 10 mm/s (30%) in normal PZ. Significant difference in repeatability of the tROI volume across series was observed (P < 0.005). The mean ADC RC% was lower than volume RC% for tROI ADC (P < 0.05). PI-RADS v2 overall assessment was highly repeatable. Multiparametric magnetic resonance imaging sequences differ in volume measurement repeatability. The mean tROI ADC is more repeatable compared with tROI volume in ADC. Repeatability of prostate ADC is comparable with that in other abdominal organs.


Nurse-administered intravitreal injections of anti-VEGF: study protocol for noninferiority randomized controlled trial of safety, cost and patient satisfaction.
Intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) now improve or stabilize visual acuity in a number of previously untreatable eye diseases, of which the main are age-related macular degeneration, retinal vein occlusion and diabetic macular edema. Most patients require multiple injections over lengthy periods of time and the prevalence of treatable conditions is increasing. Anti-VEGF IVI normally administered by physicians, therefore represent a considerable workload on ophthalmologic clinics and will continue to do so in the near future. Nurse-administered IVI may relieve this workload, but the safety, cost and patient satisfaction of such an extended role for nurses in ophthalmologic clinics has not earlier been investigated. To investigate these outcomes following independent anti-VEGF IVI by trained nurses, a noninferiority randomized controlled trial is being conducted. Patients eligible for anti-VEGF treatment, minimum 304, are recruited and randomized to IVI administration by either trained nurses or physicians. The primary outcome is safety, measured by difference in mean change in visual acuity between the two groups during an observation period of 12 months. Secondary outcomes are incidence of ocular adverse events, cost per patient and patient satisfaction. This study protocol describes the design of the first randomized controlled trial of nurse-administered IVI of anti-VEGF. The study is designed to examine safety, cost and patient satisfaction during 12 months follow-up. ClinicalTrials.gov NCT02359149 . Registered February 4, 2015.


The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms and selected other entities.
The transcription factor LMO2 is involved in vascular and hematopoietic development and hematolymphoid neoplasia. We have demonstrated that LMO2 is expressed nearly ubiquitously in native and neoplastic vasculature, including lymphatics. LMO2 reactivity is otherwise virtually absent in nonhematolymphoid tissues except in breast myoepithelium, prostatic basal cells, and secretory phase endometrial glands. Vasculature is LMO2- in adult and fetal heart, brain of older adults, hepatic sinusoids, and hepatocellular carcinoma. LMO2 is uniformly expressed in benign vascular and lymphatic neoplasms and in most malignant vascular neoplasms with the exception of epithelioid vascular neoplasms of pleura and bone. Among nonvascular neoplasms, LMO2 reactivity is present in giant cell tumor of tendon sheath, juvenile xanthogranuloma, a subset of gastrointestinal stromal tumors, small round blue cell tumors, and myoepithelial-derived neoplasms. The restricted expression pattern, nuclear localization, and crisp staining of LMO2 in paraffin blocks make it an attractive candidate for the diagnostic immunohistochemistry laboratory.


Differential allocation in a lekking bird: females lay larger eggs and are more likely to have male chicks when they mate with less related males.
The differential allocation hypothesis predicts increased investment in offspring when females mate with high-quality males. Few studies have tested whether investment varies with mate relatedness, despite evidence that non-additive gene action influences mate and offspring genetic quality. We tested whether female lekking lance-tailed manakins (Chiroxiphia lanceolata) adjust offspring sex and egg volume in response to mate attractiveness (annual reproductive success, ARS), heterozygosity and relatedness. Across 968 offspring, the probability of being male decreased with increasing parental relatedness but not father ARS or heterozygosity. This correlation tended to diminish with increasing lay-date. Across 162 offspring, egg volume correlated negatively with parental relatedness and varied with lay-date, but was unrelated to father ARS or heterozygosity. Offspring sex and egg size were unrelated to maternal age. Comparisons of maternal half-siblings in broods with no mortality produced similar results, indicating differential allocation rather than covariation between female quality and relatedness or sex-specific inbreeding depression in survival. As males suffer greater inbreeding depression, overproducing females after mating with related males may reduce fitness costs of inbreeding in a system with no inbreeding avoidance, while biasing the sex of outbred offspring towards males may maximize fitness via increased mating success of outbred sons.


Stereolithographic Surgical Guide with a Combination of Tooth and Bone Support: Accuracy of Guided Implant Surgery in Distal Extension Situation.
A distal free-end situation could result in insufficient stability of the surgical guide, and could reduce accuracy of the static guided implant surgery (sGIS). The purpose of this study was to investigate the accuracy of sGIS using a combination tooth-and-bone supported stereolithographic (SLA) surgical guide in distal extension situation. Thirty dentists, each placed three implants at the Federal Dentaire Internationale (FDI) teeth positions #46, #47 (a distal extension situation), and #36 (a single tooth gap) via the surgical guide on a model fixed to a manikin. Pre- and post-operative computed tomography (CT) images of the models were superimposed, and the positional and angular deviations of the implants were measured with metrology software. An analysis of variance (ANOVA) test was performed to evaluate the intergroup differences. No significant differences were found for all the positional and angular deviations among the three implant sites, except the bucco-lingual deviation at the implant platform in the #47 position (0.43 ± 0.19 mm) that was significantly larger than the #46 (0.21 ± 0.14 mm) and #36 (0.24 ± 0.25 mm) positions (p < 0.0001). Within the limits of this study, we conclude that, in distal extension situation of missing mandibular molars, adding a bone-supported strut in the distal part of the surgical guide can be beneficial to the accuracy of the sGIS.


Direct genetic selection of two classes of R17/MS2 coat proteins with altered capsid assembly properties and expanded RNA-binding activities.
RNA challenge phages are derivatives of bacteriophage P22 that enable direct genetic selection for a specific RNA-protein interaction. The bacteriophage P22 R17 encodes a wild-type R17 operator site and undergoes lysogenic development following infection of susceptible bacterial strains that express the R17/MS2 coat protein. A P22 R17 derivative with an OcRNA site (P22 R17 [A(-10)U]) develops lytically following infection of these strains. RNA challenge phages can be used to isolate second-site coat protein suppressors that recognize an OcRNA sequence by selecting for lysogens with a P22 R17 [Oc] phage derivative. The bacteriophage derivative P22 R17 [A(-10)U] was used in one such scheme to isolate two classes of genes that encode R17 coat proteins with altered capsid assembly properties and expanded RNA-binding characteristics. These mutations map outside the RNA-binding surface and include amino acid substitutions that interfere with interactions between coat protein dimers in the formation of the stable phage capsid. One class of mutants encodes substitutions at the highly conserved first and second positions of the mature coat protein. N-terminal sequence analysis of these mutants reveals that coat proteins with substitutions only at position 1 are defective in post-translational processing of the initiator methionine. All selected proteins possess expanded RNA-binding properties since they direct efficient lysogen formation for P22 R17 and P22 R17 [A(-10)U]; however, bacterial strains that express the protein mutants remain sensitive to lytic infection by other P22 R17 [Oc] bacteriophages. The described selection strategy provides a novel genetic approach to dissecting protein structure within RNA-binding proteins.


Comparison of decision learning models using the generalization criterion method.
It is a hallmark of a good model to make accurate a priori predictions to new conditions (Busemeyer & Wang, 2000). This study compared 8 decision learning models with respect to their generalizability. Participants performed 2 tasks (the Iowa Gambling Task and the Soochow Gambling Task), and each model made a priori predictions by estimating the parameters for each participant from 1 task and using those same parameters to predict on the other task. Three methods were used to evaluate the models at the individual level of analysis. The first method used a post hoc fit criterion, the second method used a generalization criterion for short-term predictions, and the third method again used a generalization criterion for long-term predictions. The results suggest that the models with the prospect utility function can make generalizable predictions to new conditions, and different learning models are needed for making short-versus long-term predictions on simple gambling tasks.


Human immunodeficiency virus type 1-infected blood donors: behavioral characteristics and reasons for donation. The HIV Blood Donor Study Group.
Between May 1988 and September 1989, 829 human immunodeficiency virus type 1 (HIV-1)-seropositive donors were identified from 3,919,000 units of blood donated at 20 United States (US) blood centers. Of the 829,512 (62%) were interviewed to assess behavioral characteristics of the largest subgroup, men reporting sex with men, use of the confidential unit exclusion (CUE) and reasons for donation among all donors. Among 216 men reporting sex with men, 97 percent had male and 72 percent had female sexual contact since 1978. The majority identified themselves as bisexual (29%) or heterosexual (26%). Although 61 percent of 512 donors were aware of their risk behavior at donation, including 57 percent of those infected through heterosexual transmission, only 5 percent used the CUE. Reasons for donation included failure to read carefully (46%) or comprehend (15%) the deferral materials, pressure to donate (27%), a desire to be tested for HIV-1 (15%), and a reliance on screening to identify infected blood (10%). Reasons given for a perception of being at low risk included no recent risk behaviors, infrequent risk behaviors, or modification of risk behaviors. To reach high-risk donors, centers should assess whether referral materials provide necessary medical information and are clearly written for persons with diverse cultural and language backgrounds. Staff should be encouraged to avoid the use of culturally stigmatized terms and behaviors that may be perceived as high pressure.


Immunization of knock-out α/β interferon receptor mice against high lethal dose of Crimean-Congo hemorrhagic fever virus with a cell culture based vaccine.
Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne zoonotic disease. The disease has been reported in many countries of Africa, Asia, the Middle East, and in Eurasia. During the past decade, new foci of CCHF have emerged in the Balkan Peninsula, southwest Russia, the Middle East, western China, India, Africa, and Turkey. CCHF virus produces severe hemorrhagic manifestations in humans with fatality rates up to 30%. Vaccine development efforts have been significantly hampered by a lack of animal models and therefore, no protective vaccine has been achieved. Lately, IFN α/β receptor deficient (IFNAR-/-) mice have been established as a novel small animal model of CCHF virus infection. In the present study, we found that IFNAR-/- mice highly susceptible to CCHF virus Turkey-Kelkit06 strain. Immunization with the cell culture based vaccine elicited a significant level of protection against high dose challenge (1,000 PPFU) with a homologous CCHF virus in IFNAR-/- mice.


Linking beta-catenin to androgen-signaling pathway.
The androgen-signaling pathway is important for the growth and progression of prostate cancer cells. The growth-promoting effects of androgen on prostate cells are mediated mostly through the androgen receptor (AR). There is increasing evidence that transcription activation by AR is mediated through interaction with other cofactors. beta-Catenin plays a critical role in embryonic development and tumorigenesis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Here, we demonstrate that a specific protein-protein interaction occurs between beta-catenin and AR. Unlike the steroid hormone receptor coactivator 1 (SRC1), beta-catenin showed a strong interaction with AR but not with other steroid hormone receptors such as estrogen receptor alpha, progesterone receptor beta, and glucocorticoid receptor. The ligand binding domain of AR and the NH(2) terminus combined with the first six armadillo repeats of beta-catenin were shown to be necessary for the interaction. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. Moreover, expression of E-cadherin in E-cadherin-negative prostate cancer cells results in redistribution of the cytoplasmic beta-catenin to the cell membrane and reduction of AR-mediated transcription. These data suggest that loss of E-cadherin can elevate the cellular levels of beta-catenin in prostate cancer cells, which may directly contribute to invasiveness and a more malignant tumor phenotype by augmenting AR activity during prostate cancer progression.


Mechanism of acupuncture regulating visceral sensation and mobility.
Chinese ancient medical scientists have long focused on the internal and external contacts between acupoints on the surface of the body and the viscera. The Miraculous Pivot (it is one of the earliest medical classics in China) stated, "Twelve regular channels belong to the zang-fu organs internally, and connect to the extremities and joints externally." Traditional Chinese medicine considers acupoints as defined areas where the Qi of viscera and meridians are transfused. These include the reaction points of visceral diseases on the body surface as well as the acupuncture trigger points that promote the flow of Qi and blood, and regulate visceral function. Chinese ancient medical scientists classified the specificity of the main acupoints in the body based on the meridian doctrine, which has been instructing clinical application for about 2000 years. Laws on the domino effect of acupoints have mainly focused on conclusions to clinical experiences. Indications of some acupoints exceed the practical paradigm since the excessive extension occurred during theory derivation. The current research direction on acupuncture focuses on three aspects: the effectiveness of acupuncture and moxibustion; the relevances and associations between meridians and viscera; and the physical and chemical properties and relevant physical basis of acupoints. The relevance between meridians and viscera is the central theory in the meridian doctrine, and acupoints are regarded as an important link in the relationship between meridians and viscera. Specific relationships between acupoints and target organs exist. Stimulating different acupoints on the body surface can help deal with different diseases, especially visceral diseases. In addition, acupoints have a dual function of reflecting and treating visceral diseases. There is no systemic research available on acupoint specificity, despite current knowledge and clinical experiences, which results in a weak foundation for acupuncture theory. This study focuses on the relevance and associations between meridians and viscera. A summary of the mechanisms of acupuncture regulating visceral sensation and mobility and the specific relationships between acupoints and their target organs are presented in this review.


Noncoding RNAs implication in cardiovascular diseases in the COVID-19 era.
COronaVIrus Disease 19 (COVID-19) is caused by the infection of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are respiratory, many patients also display acute myocardial injury and chronic damage to the cardiovascular system. Understanding both direct and indirect damage caused to the heart and the vascular system by SARS-CoV-2 infection is necessary to identify optimal clinical care strategies. The homeostasis of the cardiovascular system requires a tight regulation of the gene expression, which is controlled by multiple types of RNA molecules, including RNA encoding proteins (messenger RNAs) (mRNAs) and those lacking protein-coding potential, the noncoding-RNAs. In the last few years, dysregulation of noncoding-RNAs has emerged as a crucial component in the pathophysiology of virtually all cardiovascular diseases. Here we will discuss the potential role of noncoding RNAs in COVID-19 disease mechanisms and their possible use as biomarkers of clinical use.


Resistance Training during Chemotherapy with Doxorubicin.
Previous research has shown that resistance training (RT) before doxorubicin (DOX) treatment attenuates the decline in muscle dysfunction; however, the effect of RT during DOX treatment is less known. Investigate the effects of RT before and during a 4-wk course of incremental DOX treatment on skeletal muscle function. Male, Sprague-Dawley rats (N = 36) were randomly assigned to the following groups: sedentary+saline (SED + SAL), sedentary+DOX (SED + DOX), RT + SAL, or RT + DOX. The RT protocol utilized a raised cage model, which provided progressive hindlimb loading throughout the 14-wk study, whereas SED animals were kept in normal housing. Starting at week 10, DOX-treated animals received 3 mg·kg DOX weekly for 4 wk (12 mg·kg cumulative); whereas SAL-treated groups received 0.9% NaCl as a placebo. Grip strength was recorded at 0, 10, 12, and 14 wk. Ex vivo muscle function was performed on excised soleus (SOL) and extensor digitorum longus (EDL) from the right hind limb 5 d after the last injection and were analyzed for expression of creatine kinase (CK) and creatine transporters. SED + DOX-treated animals had significantly lower EDL mass compared with SED + SAL- and RT + DOX-treated animals. Grip strength, EDL maximal force, and EDL force development were significantly lower in SED + DOX-treated animals compared with RT + SAL and SED + SAL. No significant differences in EDL function were found between RT + DOX and RT + SAL animals. DOX treatment reduced expression of CK in the SOL, which abated with RT. Low-intensity RT may attenuate the decline in skeletal muscle function during incremental DOX treatment.


The primary care physician's role in caring for internationally adopted children.
The rate of international adoption in the United States has been increasing. Internationally. adopted children have various medical, psychological, and developmental issues that need to be evaluated and addressed by primary care physicians. Full histories and physical examinations, developmental assessments, and screening tests are necessary for such children. Family concerns and cultural differences between the child and the adoptive family need to be addressed as well.


Ce(iv)-centered charge-neutral perovskite layers topochemically derived from anionic [CeTa2O7]- layers.
Layered perovskites have been extensively investigated in many research fields, such as electronics, catalysis, optics, energy, and magnetics, because of the fascinating chemical properties that are generated by the specific structural features of perovskite frameworks. Furthermore, the interlayers of these structures can be chemically modified through ion exchange to form nanosheets. To further expand the modification of layered perovskites, we have demonstrated an advance in the new structural concept of layered perovskite "charge-neutral perovskite layers" by manipulating the perovskite layer itself. A charge-neutral perovskite layer in [CeIVTa2O7] was synthesized through a soft chemical oxidative reaction based on anionic [CeIIITa2O7]- layers. The Ce oxidation state for the charge-neutral [CeIVTa2O7] layers was found to be tetravalent by X-ray absorption fine structure (XAFS) analysis. The atomic arrangements were determined through scattering transmission electron microscopy and extended XAFS (EXAFS) analysis. The framework structure was simulated through density functional theory (DFT) calculations, the results of which were in good agreement with those of the EXAFS spectra quantitative analysis. The anionic [CeIIITa2O7]- layers exhibited optical absorption in the near infrared (NIR) region at approximately 1000 nm, whereas the level of NIR absorption decreased in the [CeIVTa2O7] charge-neutral layer due to the disappearance of the Ce 4f electrons. In addition, the chemical reactivity of the charge-neutral [CeIVTa2O7] layers was investigated by chemical reduction with ascorbic acid, resulting in the reduction of the [CeIVTa2O7] layers to form anionic [CeIIITa2O7]- layers. Furthermore, the anionic [CeIIITa2O7]- layers exhibited redox activity which the Ce in the perovskite unit can be electrochemically oxidized and reduced. The synthesis of the "charge-neutral" perovskite layer indicated that diverse features were generated by systematically tuning the electronic structure through the redox control of Ce; such diverse features have not been found in conventional layered perovskites. This study could demonstrate the potential for developing innovative, unique functional materials with perovskite structures.


High frequency of microsatellites in S. cerevisiae meiotic recombination hotspots.
Microsatellites are highly abundant in eukaryotic genomes but their function and evolution are not yet well understood. Their elevated mutation rate makes them ideal markers of genetic difference, but high levels of unexplained heterogeneity in mutation rates among microsatellites at different genomic locations need to be elucidated in order to improve the power and accuracy of the many types of study that use them as genetic markers. Recombination could contribute to this heterogeneity, since while replication errors are thought to be the predominant mechanism for microsatellite mutation, meiotic recombination is involved in some mutation events. There is also evidence suggesting that microsatellites could function as recombination signals. The yeast S. cerevisiae is a useful model organism with which to further explore the link between microsatellites and recombination, since it is very amenable to genetic study, and meiotic recombination hotspots have been mapped throughout its entire genome. We examined in detail the relationship between microsatellites and hotspots of meiotic double-strand breaks, the precursors of meiotic recombination, throughout the S. cerevisiae genome. We included all tandem repeats with motif length (repeat period) between one and six base pairs. Long, short and two-copy arrays were considered separately. We found that long, mono-, di- and trinucleotide microsatellites are around twice as frequent in hot than non-hot intergenic regions. The associations are weak or absent for repeats with less than six copies, and also for microsatellites with 4-6 base pair motifs, but high-copy arrays with motif length greater than three are relatively very rare throughout the genome. We present evidence that the association between high-copy, short-motif microsatellites and recombination hotspots is not driven by effects on microsatellite distribution of other factors previously linked to both recombination and microsatellites, including transcription, GC-content and transposable elements. Our findings suggest that a mutation bias relating to recombination hotspots causing repeats to form and grow, and/or regulation of a subset of hotspots by simple sequences, may be significant processes in yeast. Some previous evidence has cast doubt on both of these possibilities, and as a result they have not been explored on a large scale, but the strength of the association we report suggests that they deserve further experimental testing.


A peroxisome proliferator-activated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregulatory loop in adipocyte mitochondrial function.
Peroxisome proliferator-activated receptor γ (PPARγ) activation induces adipogenesis and also enhances lipogenesis, mitochondrial activity, and insulin sensitivity in adipocytes. Whereas some studies implicate PPARγ coactivator 1α (PGC-1α) in the mitochondrial effect, the mechanisms involved in PPARγ regulation of adipocyte mitochondrial function are not resolved. PPARγ-activating ligands (thiazolidinediones (TZDs)) are important insulin sensitizers and were recently shown to indirectly induce PGC-1β transcription in osteoclasts. Here, we asked whether similar effects occur in adipocytes and show that TZDs also strongly induce PGC-1β in cultured 3T3-L1 cells. This effect, however, differs from the indirect effect proposed for bone and is rapid and direct and involves PPARγ interactions with an intronic PPARγ response element cluster in the PGC-1β locus. TZD treatment of cultured adipocytes results in up-regulation of mitochondrial marker genes, and increased mitochondrial activity and use of short interfering RNA confirms that these effects require PGC-1β. PGC-1β did not participate in PPARγ effects on adipogenesis or lipogenesis, and PGC-1β knockdown did not alter insulin-responsive glucose uptake into 3T3-L1 cells. Similar effects on PGC-1β and mitochondrial gene expression are seen in vivo; fractionation of obese mouse adipose tissue reveals that PPARγ and PGC-1β, but not PGC-1α, are coordinately up-regulated in adipocytes relative to preadipocytes and that TZD treatment induces PGC-1β and mitochondrial marker genes in adipose tissue of obese mice. We propose that PPARγ directly induces PGC-1β expression in adipocytes and that this effect regulates adipocyte mitochondrial activity.


Determination of amino acids in pomegranate juices and fingerprint for adulteration with apple juices.
A new chiral micellar electrokinetic chromatography-laser induced fluorescence (MEKC-LIF) method was developed using sodium dodecylbenzene sulphonate (SDBS) as surfactant for the determination of chiral amino acids in pomegranate juices. The use of SDBS as the micellar medium enhanced the fluorescence intensities of amino acids derivatised with fluorescein isothiocyanate (FITC). The amino acid profile of pomegranate juices was compared to apple amino acids and l-Asn was proposed as a marker for the adulteration of pomegranate juices with apple juices.


[A case of necrotizing colitis presenting with hepatic portal venous gas and pneumatosis intestinalis].
Hepatic portal venous gas is a very rare radiologic sign which is characterized by gas accumulation in the portal venous circulation. Pneumatosis intestinalis is also very rare and is characterized by multiple air cysts in the serosal or submucosal layers of the gastrointestinal tract walls. These two findings are caused by various pathological conditions and can develop individually or simultaneously. The latter is clinically more significant because it is frequently related to bowel ischemia or necrosis, and represents a poor prognosis. However, prognosis is more influenced by the severity of underlying disease rather than hepatic portal venous gas or pneumatosis intestinalis itself. If bowel ischemia or necrosis is the primary cause, emergency operation is very important to improve patient's prognosis. Herein, we report a case of necrotizing colitis presenting as hepatic portal venous gas and pneumatosis intestinalis which was successfully managed by early surgery.


Multilevel Risk and Protective Factors for Intimate Partner Violence Among African, Asian, and Latina Immigrant and Refugee Women: Perceptions of Effective Safety Planning Interventions.
Immigrant and refugee women are at high risk for intimate partner violence (IPV) and intimate partner homicide (IPH). Given the growing number of immigrants and refugees in the US and the concerns about IPV and IPH among immigrant and refugee groups, this paper aims to identify survivors and practitioners' perceptions of a) common and culturally specific risk and protective factors for IPV and IPH for immigrant and refugee women and b) areas of safety planning interventions for survivors who are at risk for severe or lethal violence by an intimate partner. Qualitative data for this multi-site study were collected from women and practitioners residing in seven geographically diverse US locations. Eighty-three in-depth interviews were conducted with adult immigrant and refugee survivors of IPV, who identified as Asian (n=30), Latina (n=30), and African (n=23). Additionally, nine focus groups and five key informant interviews were conducted with practitioners (n=62) who serve immigrant and refugee survivors of IPV. Results revealed multilevel risk and protective factors for IPV/IPH found at the societal-level (e.g., patriarchal cultural norms), relationship-level (e.g., partner abusive behaviors), and individual-level (e.g., acculturation in the US). These findings can inform the development of culturally responsive risk assessment and safety planning interventions across legal, social service, and healthcare settings.


[Complete remission of nephrotic syndrome and improvement of renal function in a patient with light chain deposition disease following high dose chemotherapy with transplantation of autologous haematopoietic stem cells. A case study and review of literature].
Light chain deposition disease (LCDD) damages most frequently kidneys, and less frequently other organs. The incidence of LCDD is lower than the incidence of AL-amyloidosis. Symmetric swelling of both legs was the first sign of nephrotic syndrome with renal insufficiency in our female patient. Renal biopsy specimen revealed the diagnosis of LCDD. Bone marrow biopsy contained 40% of plasma cells. Bone survey showed no osteolytic changes. These findings confirmed the diagnosis of multiple myeloma (MM) Durie Salmon stage IB with LCDD. The patient was initially treated with 4 cycles of VAD (vinkristine, adriamycine, dexamethasone) chemotherapy with no response. Followed collection of peripheral haematopoietic stem cells and later high dose chemotherapy with reduced dose of melphalan 140 mg/sqm and autologous peripheral haematopoietic stem cells transplantation. Melphalan dose was reduced because of renal insufficiency (serum creatinine 290 micromol/l) before application of conditioning regimen. High dose therapy was complicated by with deterioration of renal function, creatinine increased to 600 micromol/l. Worsening of renal function was most likely caused by nephrotoxicity of melphalan in nephrotic syndrome. This has been previously described in patients with AL-amyloidosis, and nephrotic syndrome who were treated with high dose melphalan. This phenomenon was entitled "post conditioning renal insufficiency". Hypoalbuminemia hypoproteinemia and reduced intravascular volume and renal damage caused by amyloid deposits as well as probably, amorphous non-amyloid deposits of monoclonal immunoglobulin are likely to have contributed to nephrotoxicity of the high dose of melphalan. However, worsening of renal insufficiency was facilitated by the mucositis-associated sepsis. Follow-up examination one month after high dose chemotherapy showed complete remission, that was confirmed by further examinations. In the course of the first year after high dose chemotherapy renal function gradually improved and nephrotic syndrome completely disappeared (complete kidney remission). Proteinuria declined to 2-3 g/24 hours and glomerular filtration slowly improved. Three years after high dose chemotherapy the patient is still in complete remission of multiple myeloma and free of nephrotic syndrome, with slightly increased creatinine (160 micromol/l) that, nevertheless, has had an improving tendency over last 3 years. The present case study illustrates accomplishment of complete haematological remission with high dose chemotherapy followed by autologous haematopoietic stem cells transplantation despite complete resistance of the disease to the standard chemotherapy VAD in a patient with MM and LCDD. We draw the reader's attention to the possibility of nephrotoxic effects of high dose melphalan (post conditioning renal insufficiency) in patients with nephrotic syndrome caused by light chain deposits as AL-amyloid or amorphous light chains deposits (LCDD)and we document the importance of plasma free light chain detection.


Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.
Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.


Potential of Pm11 antimicrobial peptide against bovine mastitis pathogens.
To investigate an alternative treatment for bovine mastitis by using Pm11 antimicrobial peptide. 5 bovine mastitis pathogens that were previously isolated from cows affected by either clinical or subclinical mastitis. The current study introduces Pm11 antimicrobial peptide as an alternative treatment for bovine mastitis. The antibacterial activity of Pm11 was tested against Escherichia coli strain SCM1249, Klebsiella spp strain SCM1282, Staphylococcus aureus strain CM967, Streptococcus agalactiae strain SCM1084, and Streptococcus uberis strain SCM1310 using minimum bactericidal concentrations (MBCs) and time-kill kinetics. The pathogens' morphological changes were demonstrated using a scanning electron microscope (SEM). The cytotoxicity of Pm11 was assessed using the minimum hemolytic concentration assay. MBCs ranged from 2.5 to 10 μM and IC50 ranged from 0.32 to 2.07 μM. Time-kill kinetics at MBC demonstrated that Pm11 reduced viable cell counts of S agalactiae strain SCM1084 and S uberis strain SCM1310 from 105 to 0 CFU/mL within 1 h. E coli strain SCM1249 and S aureus strain CM967 were reduced from 105 to 0 CFU/mL within 4 h. The average Pm11-induced hemolytic activity was < 10% for all Pm11 concentrations tested except at the maximum concentration tested (160 μM: 10.19 ± 2.29%). Based on SEM, Pm11 induced morphological and cellular changes in S aureus and E coli. Pm11 antimicrobial peptide demonstrated in vitro antibacterial activity against the common bovine mastitis pathogens E coli, S aureus, S agalactiae, and S uberis, except Klebsiella spp, and should be further investigated in vivo.


Accurate measurement of the chirality of WS2 nanotubes.
We describe the structural parameters and atomic positions of a single-walled WS2 nanotube. The structure factor is calculated in detail using analytic expressions for both single-walled and multi-walled WS2 nanotubes. A zoning scheme has been developed to obtain the ratio m/n from the electron diffraction patterns. The procedure for determination of the chiral indices of both single-walled and multi-walled WS2 nanotubes and the tilt angle is illustrated in detail for either normal incidence or inclined incidence. As an example of application, the determination of the chiral indices of a five-shell WS2 nanotube was carried out and the tilt angle was obtained as 17.7°. The method developed here is useful and valid to determine the atomic structure of WS2 nanotubes.


Fast maximum-likelihood image-restoration algorithms for three-dimensional fluorescence microscopy.
We have evaluated three constrained, iterative restoration algorithms to find a fast, reliable algorithm for maximum-likelihood estimation of fluorescence microscopic images. Two algorithms used a Gaussian approximation to Poisson statistics, with variances computed assuming Poisson noise for the images. The third method used Csiszar's information-divergence (I-divergence) discrepancy measure. Each method included a nonnegativity constraint and a penalty term for regularization; optimization was performed with a conjugate gradient method. Performance of the methods was analyzed with simulated as well as biological images and the results compared with those obtained with the expectation-maximization-maximum-likelihood (EM-ML) algorithm. The I-divergence-based algorithm converged fastest and produced images similar to those restored by EM-ML as measured by several metrics. For a noiseless simulated specimen, the number of iterations required for the EM-ML method to reach a given log-likelihood value was approximately the square of the number required for the I-divergence-based method to reach the same value.


The Timing of Utterance Planning in Task-Oriented Dialogue: Evidence from a Novel List-Completion Paradigm.
In conversation, interlocutors rarely leave long gaps between turns, suggesting that next speakers begin to plan their turns while listening to the previous speaker. The present experiment used analyses of speech onset latencies and eye-movements in a task-oriented dialogue paradigm to investigate when speakers start planning their responses. German speakers heard a confederate describe sets of objects in utterances that either ended in a noun [e.g., Ich habe eine Tür und ein Fahrrad ("I have a door and a bicycle")] or a verb form [e.g., Ich habe eine Tür und ein Fahrrad besorgt ("I have gotten a door and a bicycle")], while the presence or absence of the final verb either was or was not predictable from the preceding sentence structure. In response, participants had to name any unnamed objects they could see in their own displays with utterances such as Ich habe ein Ei ("I have an egg"). The results show that speakers begin to plan their turns as soon as sufficient information is available to do so, irrespective of further incoming words.


Evidence To Support Continuation of Statin Therapy in Patients with Staphylococcus aureus Bacteremia.
In addition to cholesterol-lowering capabilities, statins possess anti-inflammatory and immunomodulatory effects. We sought to quantify the real-world impact of different statin exposure patterns on clinical outcomes in Staphylococcus aureus bacteremia. We conducted a retrospective cohort study among hospitalized patients with positive S. aureus blood cultures receiving appropriate antibiotics within 48 h of culture collection (Veterans Affairs hospitals, 2002 to 2013). Three statin exposure groups were compared to nonusers: pretreated statin users initiating therapy in the 30 days prior to culture and either (i) continuing statin therapy after culture or (ii) not continuing after culture, and (iii) de novo users initiating at culture. Nonusers included patients without statins in the year prior to culture through discharge. Propensity score-matched Cox proportional hazards regression models were developed. We were able to balance significantly different baseline characteristics using propensity score matching for pretreated without continuation (n = 331), pretreated with continuation (n = 141), and de novo (n = 177) statin users compared to nonusers. We observed a significantly lower 30-day mortality rate (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.25 to 0.84; number needed to treat [NNT], 10) among pretreated and continued statin users, while protective effects were not observed in de novo (HR, 1.04; 95% CI, 0.60 to 1.82; NNT, undefined) or pretreated but not continued (HR, 0.92; 95% CI, 0.64 to 1.32; NNT, 47) users. In our national cohort study among patients with S. aureus bacteremia, continuation of statin therapy among incident statin users was associated with significant beneficial effects on mortality, including a 54% lower 30-day mortality rate.


Phospholipid growth factors and corneal wound healing.
In many tissue types, wound healing involves cell division and migration over and into the wound area to cover and remodel the wound. LPA and other members of the phospholipid lipid growth factor (PLGF) family stimulate many of the activities involved in wound healing. In the rabbit cornea, we have found that keratocytes from wounded corneas have a volume-activated Cl- current activated by LPA and alkenyl-LPA. This current is minimally activated by cyclic PA and SPC, and is not activated by LPA in cells from uninjured corneas. Biochemical examination of PLGFs in aqueous humor and lacrimal fluid before and after wounding identified LPA, alkenyl-GP, PA, and lyso PS, with elevated PLGF activity after wounding. In recent experiments examining human corneal cell lines and cultured cells using RT-PCR, we found mRNA for EDG receptors 1-5, with an apparent increase in EDG-3, -4, and -5 following brief SDS application to cell lines, and EDG receptors 2-5 induction in late-passage human corneal epithelial cells. This work points to a significant role for PLGFs in the corneal wound-healing process.


How to find simple and accurate rules for viral protease cleavage specificities.
Proteases of human pathogens are becoming increasingly important drug targets, hence it is necessary to understand their substrate specificity and to interpret this knowledge in practically useful ways. New methods are being developed that produce large amounts of cleavage information for individual proteases and some have been applied to extract cleavage rules from data. However, the hitherto proposed methods for extracting rules have been neither easy to understand nor very accurate. To be practically useful, cleavage rules should be accurate, compact, and expressed in an easily understandable way. A new method is presented for producing cleavage rules for viral proteases with seemingly complex cleavage profiles. The method is based on orthogonal search-based rule extraction (OSRE) combined with spectral clustering. It is demonstrated on substrate data sets for human immunodeficiency virus type 1 (HIV-1) protease and hepatitis C (HCV) NS3/4A protease, showing excellent prediction performance for both HIV-1 cleavage and HCV NS3/4A cleavage, agreeing with observed HCV genotype differences. New cleavage rules (consensus sequences) are suggested for HIV-1 and HCV NS3/4A cleavages. The practical usability of the method is also demonstrated by using it to predict the location of an internal cleavage site in the HCV NS3 protease and to correct the location of a previously reported internal cleavage site in the HCV NS3 protease. The method is fast to converge and yields accurate rules, on par with previous results for HIV-1 protease and better than previous state-of-the-art for HCV NS3/4A protease. Moreover, the rules are fewer and simpler than previously obtained with rule extraction methods. A rule extraction methodology by searching for multivariate low-order predicates yields results that significantly outperform existing rule bases on out-of-sample data, but are more transparent to expert users. The approach yields rules that are easy to use and useful for interpreting experimental data.


Distributed Raman amplification using ultra-long fiber laser with a ring cavity: characteristics and sensing application.
Distributed Raman amplification (DRA) based on ultra-long fiber laser (UL-FL) pumping with a ring cavity is promising for repeaterless transmission and sensing. In this work, the characteristics (including gain, nonlinear impairment and noise figure) for forward and backward pumping of the ring-cavity based DRA scheme are fully investigated. Furthermore, as a typical application of the proposed configuration, ultra-long-distance distributed sensing with Brillouin optical time-domain analysis (BOTDA) over 142.2 km fiber with 5m spatial resolution and ± 1.5 °C temperature uncertainty is achieved, without any repeater. The key point for the significant performance improvement is the system could offer both of uniform gain distribution and considerably suppressed pump-probe relative intensity noise (RIN) transfer, by optimized design of system structure and parameters.