Understanding Conditionals in the East: A Replication Study of With Easterners.
The new probabilistic approaches to the natural language conditional imply that there is a parallel relation between indicative conditionals (ICs) "if s then b" and conditional bets (CBs) "I bet $1 that if s then b" in two aspects. First, the probability of an IC and the probability of winning a CB are both the conditional probability, P(s|b). Second, both an IC and a CB have a third value "void" (neither true nor false, neither wins nor loses) when the antecedent is false (¬s). These aspects of the parallel relation have been found in Western participants. In the present study, we investigated whether this parallel is also present in Eastern participants. We replicated the study of Politzer et al. (2010) with Chinese and Japanese participants and made two predictions. First, Eastern participants will tend to engage in more holistic cognition and take all possible cases, including ¬s, into account when they judge the probability of conditional: Easterners may assess the probability of antecedent s out of all possible cases, P(s), and then may focus on consequent b out of s, P(b|s). Consequently, Easterners may judge the probability of the conditional, and of winning the bet, to be P(s) ∗ P(b|s) = P(s & b), and false/losing the bet as P(s) ∗ P(¬b|s) = P(s & ¬b). Second, Eastern participants will tend to be strongly affected by context, and they may not show parallel relationships between ICs and CBs. The results indicate no cultural differences in judging the false antecedent cases: Eastern participants judged false antecedent cases as not making the IC true nor false and as not being winning or losing outcomes. However, there were cultural differences when asked about the probability of a conditional. Consistent with our hypothesis, Eastern participants had a greater tendency to take all possible cases into account, especially in CBs. We discuss whether these results can be explained by a hypothesized tendency for Eastern people to think in more holistic and context-dependent terms than Western people.


Canada's health care system provides lessons for NPs.
With increasing economic pressures, swaying public opinion and new government policies rationing health care resources, nurses in Canada are again challenging physicians for room to practice as nurse practitioners. Although the last Canadian nurse practitioner program was discontinued in 1983, and it was argued that the death of the role was inevitable in Canada's health care system, nurse practitioners have not vanished. Social plans in the United States are drawing heavily on the Canadian model of universal access and a government-funded health care system, and dramatic changes are taking place in Ontario's health care system. Now more than ever it is important that nurse practitioners understand Canada's health care system, why the NP role in Ontario has not been highly successful, and why the time is right for reintroduction of nurse practitioners into Ontario's health care system.


Quinine and severe falciparum malaria in late pregnancy.
Quinine dihydrochloride was given intravenously to 12 women with severe falciparum malaria in the third trimester of pregnancy. The initial dose consisted of 10 or 20 mg salt/kg over 4 h and was followed by 10 mg salt/kg every 8 h until patients were fit to swallow, when quinine sulphate tablets were given. Uterine activity showed little or no change despite rising quinine concentrations. Of 3 patients in labour, 2 proceeded normally while a third had a successful caesarean section for fetal distress. Late (type II) decelerations of the fetal heart rate were recorded in 6 patients before treatment but in most patients signs of fetal distress diminished as the maternal temperature fell. Hypoglycaemia and hyperinsulinaemia developed in 7 patients, in 2 before quinine was started. The important toxic effect of quinine in late pregnancy is not an oxytocic action but rather its capacity to release insulin.


Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues.
The growth and dynamics of epithelial tissues govern many morphogenetic processes in embryonic development. A recent quantitative transition in data acquisition, facilitated by advances in genetic and live-imaging techniques, is paving the way for new insights to these processes. Computational models can help us understand and interpret observations, and then make predictions for future experiments that can distinguish between hypothesised mechanisms. Increasingly, cell-based modelling approaches such as vertex models are being used to help understand the mechanics underlying epithelial morphogenesis. These models typically seek to reproduce qualitative phenomena, such as cell sorting or tissue buckling. However, it remains unclear to what extent quantitative data can be used to constrain these models so that they can then be used to make quantitative, experimentally testable predictions. To address this issue, we perform an in silico study to investigate whether vertex model parameters can be inferred from imaging data, and explore methods to quantify the uncertainty of such estimates. Our approach requires the use of summary statistics to estimate parameters. Here, we focus on summary statistics of cellular packing and of laser ablation experiments, as are commonly reported from imaging studies. We find that including data from repeated experiments is necessary to generate reliable parameter estimates that can facilitate quantitative model predictions.


Bouncing between model and data: stability, passivity, and optimality in hybrid dynamics.
Rhythmically bouncing a ball with a racket is a seemingly simple task, but it poses all the challenges critical for coordinative behavior: perceiving the ball's trajectory to adapt position and velocity of the racket for the next ball contact. To gain insight into the underlying control strategies, the authors conducted a series of studies that tested models with experimental data, with an emphasis on deriving model-based hypotheses and trying to falsify them. Starting with a simple dynamical model of the racket and ball interactions, stability analyses showed that open-loop dynamics affords dynamical stability, such that small perturbations do not require corrections. To obtain this passive stability, the ball has to be impacted with negative acceleration--a strategy that subjects adopted in a variety of conditions at steady state. However, experimental tests that applied perturbations revealed that after perturbations, subjects applied active perceptually guided corrections to reestablish steady state faster than by relying on the passive model's relaxation alone. Hence, the authors derived a model with active control based on optimality principles that considered each impact as a separate reaching-like movement. This model captured some additional features of the racket trajectory but failed to predict more fine-grained aspects of performance. The authors proceed to present a new model that accounts not only for fine-grained behavior but also reconciles passive and active control approaches with new predictions that will be put to test in the next set of experiments.


Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis.
For reasons that are not well understood, central nervous system repair in multiple sclerosis is often minimal. We present evidence, in a murine model of chronic progressive multiple sclerosis, that genetic factors can substantially influence remyelination, axonal integrity, and neurologic function. Four inbred mouse strains, SJL, B10.D1-H2(q), FVB, and SWR, developed extensive inflammatory demyelination by 3 months after infection with Theiler's murine encephalomyelitis virus. Demyelination continued lifelong in SJL and B10.D1-H2(q) mice, accompanied by axonal injury, minimal remyelination, and progressive motor dysfunction. In contrast, FVB and SWR mice showed less axonal injury, progressive remyelination, and stabilization of motor function. Genetic dominance of the reparative traits was demonstrated by crossing remyelinating strains (FVB and SWR) with nonremyelinating strains (SJL and B10.D1-H2(q)). All F1 mice developed a phenotype identical to FVB and SWR, showing extensive remyelination, partial preservation of axons, and preserved motor function. Analyses of viral RNA and antigen, immune cell infiltration, and antiviral antibody titers did not predict the phenotypic differences between strains. These results highlight the significant extent to which hereditary factors can control disease course and demonstrate that the switch from a pathogenic to a reparative phenotype can occur even after prolonged inflammatory demyelination.


Applying Bayesian network modelling to understand the links between on-farm biosecurity practice during the 2007 equine influenza outbreak and horse managers' perceptions of a subsequent outbreak.
Australia experienced its first ever outbreak of equine influenza in August 2007. Horses on 9359 premises were infected over a period of 5 months before the disease was successfully eradicated through the combination of horse movement controls, on-farm biosecurity and vaccination. In a previous premises-level case-control study of the 2007 equine influenza outbreak in Australia, the protective effect of several variables representing on-farm biosecurity practices were identified. Separately, factors associated with horse managers' perceptions of the effectiveness of biosecurity measures have been identified. In this analysis we applied additive Bayesian network modelling to describe the complex web of associations linking variables representing on-farm human behaviours during the 2007 equine influenza outbreak (compliance or lack thereof with advised personal biosecurity measures) and horse managers' perceptions of the effectiveness of such measures in the event of a subsequent outbreak. Heuristic structure discovery enabled identification of a robust statistical model for 31 variables representing biosecurity practices and perceptions of the owners and managers of 148 premises. The Bayesian graphical network model we present statistically describes the associations linking horse managers' on-farm biosecurity practices during an at-risk period in the 2007 outbreak and their perceptions of whether such measures will be effective in a future outbreak. Practice of barrier infection control measures were associated with a heightened perception of preparedness, whereas horse managers that considered their on-farm biosecurity to be more stringent during the outbreak period than normal practices had a heightened perception of the effectiveness of other measures such as controlling access to the premises. Past performance in an outbreak setting may indeed be a reliable predictor of future perceptions, and should be considered when targeting infection control guidance to horse owners and managers.


Comparison between helical computed tomography angiography and intraoperative findings.
Live donor nephrectomy has gained popularity on account of the laparoscopic technique, to overcome a small donor pool. Laparoscopic donor nephrectomy requires a precise study of the vascular and morphological renal anatomy, as laparoscopy is technically challenging due to the limited field of vision. In-depth knowledge of the renal anatomy before a laparoscopic procedure is essential for a successful transplant. The left kidney is preferred over the right even in cases of multiple vessels because of the long renal vein, which requires precise preoperative vascular mapping. Helical computerized tomography (CT) angiography, with its axial, coronal, and 3D reconstruction, gives a better understanding of renal anatomy. There are instances where the helical CT findings are misleading and less informative in a small number of cases. This study highlights a case study of the helical CT findings compared with the intraoperative findings of 200 live donors, who underwent laparoscopic donor nephrectomy, and the renal anatomy has been understood at the same time. 1. To compare the helical CT findings on the operated side with the intraoperative findings. 2. To analyze the CT findings. Two hundred cases of laparoscopic transperitoneal donor nephrectomy were included in this study. Chi square test was the statistical test used to compare the findings between CT and the intraoperative data. The axial, coronal, and 3D images of the CT findings were on par with the intraoperative findings in most of the cases. Incidental findings help in the better planning of surgery. Multiple vessels on the left side are preferred over the right sided normal anatomy; with not much technical difficulty with the aid of a helical CT. Male donors had more incidences of multiple vessels, gonadal vein, Retroaortic Renal Vein (RARV), lumbar vein, and duplication of ureter, compared to females. Furthermore, these variations are more in the left side donors. Ninety-two percent of the cases in this study are left-sided donors. The helical CT finding shows that renal vein variations are more on the right side. Helical CT is important in delineating the arterial, venous, and ureteral anatomy and can show the important incidental findings. Left renal donors and males have more variations in their renal anatomy. Technically challenging laparoscopic nephrectomy on the multiple-vessel-side donor is possible with the aid of helical CT. The importance of the CT in evaluating donor renal anatomy for a technically challenging laparoscopic donor nephrectomy is commendable.


The control of chlorophyll catabolism and the status of yellowing as a biomarker of leaf senescence.
The pathway of chlorophyll catabolism during leaf senescence is known in a fair amount of biochemical and cell biological detail. In the last few years, genes encoding a number of the catabolic enzymes have been characterized, including the key ring-opening activities, phaeophorbide a oxygenase (PaO) and red chlorophyll catabolite reductase (RCCR). Recently, a gene that modulates disassembly of chlorophyll-protein complexes and activation of pigment ring-opening has been isolated by comparative mapping in monocot species, positional cloning exploiting rice genomics resources and functional testing in Arabidopsis. The corresponding gene in pea has been identified as Mendel's I locus (green/yellow cotyledons). Mutations in this and other chlorophyll catabolic genes have significant consequences, both for the course of leaf senescence and senescence-like stress responses, notably hypersensitivity to pathogen challenge. Loss of chlorophyll can occur via routes other than the PaO/RCCR pathway, resulting in changes that superficially resemble senescence. Such 'pseudosenescence' responses tend to be pathological rather than physiological and may differ from senescence in fundamental aspects of biochemistry and regulation.


The epidemiology and prevention of suicide by hanging: a systematic review.
Hanging is one of the most commonly used methods for suicide worldwide. In England and a number of other countries, its incidence has increased over the last 30 years. This review summarizes the published literature on suicide by hanging. The focus is on its epidemiology in England and on identifying potential means of prevention. We searched Medline (1966-2003), Embase (1980-2003), CINAHL (1982-2003) and PsycINFO (1967-2003). As considerable research on suicides occurring in prisons and psychiatric hospitals in England and Wales has been carried out by the National Confidential Inquiry into Suicide and Homicide (Manchester) and the Prison Service's Safer Custody Group, we obtained additional information from these sources. Only a small proportion (around 10%) of hanging suicides occur in the controlled environments of hospitals, prisons, and police custody; the remainder occur in the community. The most commonly used ligatures (rope, belts, flex) and ligature points (beams, banisters, hooks, door knobs, and trees) are widely available; thus prevention strategies focused around restriction of access to means of hanging are of limited value. Around 50% of hanging suicides are not fully suspended--ligature points below head level are commonly used. Case fatality following attempted suicide by hanging is around 70%; the majority (80-90%) of those who reach hospital alive survive. Strategies to reduce suicide by hanging should focus on the prevention of suicide in controlled environments, the emergency management of 'near-hanging' and on the primary prevention of suicide in general. More research is required to better understand the recent rise in popularity of this method.


Effects of familial and non-familial warmth during childhood and adolescence on sexual-orientation disparities in alcohol use trajectories and disorder during emerging adulthood.
We investigated sexual-orientation differences in typologies of self-reported familial and non-familial warmth in childhood (before age 11) and adolescence (ages 11-17); and tested whether warmth explained sexual minority emerging adults' (ages 18-25) heightened odds of having heavier alcohol use trajectories (AUTs) and heightened risk for past-year alcohol use disorder (AUD) compared to completely heterosexuals. Using self-reported data from the U.S.-based Growing Up Today Study cohort, latent class analyses identified typologies of familial and non-familial warmth during childhood and adolescence. Multivariable regression models tested our objectives. Six warmth classes emerged, including: High-High (i.e., high familial and high non-familial warmth, respectively); High-Moderate; Moderate-Moderate; Moderate-Occasional; Occasional-Occasional; and Low-Low. Among women, sexual minorities had higher odds than completely heterosexuals of being in the Moderate-Moderate, Moderate-Occasional, and Occasional-Occasional versus the High-High warmth class. There were not significant associations between sexual orientation and warmth classes for men. Lower warmth classes were generally associated with greater past-year AUD, and mediated heightened disparities in AUD for sexual minority women versus completely heterosexual women (4.3% mediated), but not among men. Warmth classes were generally unassociated with AUTs, and did not mediate sexual-orientation differences in AUTs. Lower warmth was associated with greater alcohol-related problems, but not alcohol use itself. Warmth explained a small proportion of AUD disparities for sexual minority women-but not for men.


Changes In The Equity Of US Health Care Financing In The Period 2005-16.
Spending on health care in the United States amounted to 17.9 percent of gross domestic product in 2017. Households paid for this care through out-of-pocket medical spending and a complex mix of out-of-pocket premiums, employer premium contributions, taxes, and subsidies that combined to finance private employer-sponsored insurance, nongroup insurance, and multiple public insurance programs. Our analysis examined the impact of this complex system of health care financing on households in the period 2005-16, tracking how economic and policy changes affected incidence-that is, the amount paid to finance health care, either directly or indirectly, by households as a share of their pretax income. Health care financing was regressive at the start of our study period, with households in the bottom 20 percent of income paying 26.8 percent of their income compared to about half that amount for those with income in the top 1 percent. By 2016 incidence had become approximately proportional (the same percentage across all income levels). In part, these results reflect increases in coverage through Medicaid and the Affordable Care Act Marketplaces, which are progressively financed through the federal tax system.


The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.
To identify indications for hysterectomy in patients with gestational trophoblastic neoplasia (GTN) and to evaluate outcomes of hysterectomy in those patients. Patients who underwent hysterectomy were identified utilizing hospital medical records and the New England Trophoblastic Disease Center (NETDC) database from January 1, 1959-January 1, 2009. Demographic data as well as indication for hysterectomy, stage, World Health Organization score, chemotherapeutic regimens and outcomes were recorded. We further stratified our population into patients with hysterectomies before and after 1980 to assess how indications for and outcomes after hysterectomy may have changed at our institution over time. A total of 98 patients were identified to have undergone hysterectomy for GTN. In the entire cohort 85% (n = 83) achieved remission and 48% (n = 47) required chemotherapy after hysterectomy. Among the patients in the early cohort (n = 49), indications for hysterectomy included 15 (31%) for primary definitive management, 14 (29%) for chemotherapy resistant disease, 14 (29%) for bleeding and 6 (11%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 9 (64%) achieved remission. In the more recent cohort (n = 49) indications for hysterectomy included 24 (49%) for primary definitive management, 19 (39%) for drug-resistant disease, 4 (8%) for bleeding and 2 (4%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 16 (84%) achieved remission. There was a statistically significant decline in the number of hysterectomies performed for bleeding. Hysterectomy was performed for bleeding in the early cohort (1959-1980) in 14 (29%) of 49 patients but in only 4 (8%) of 49 patients in the later cohort (1981-2009) (p = 0.02). During the years 1959-2009 the number of hysterectomies performed for GTN at the NETDC has remained stable. However, at our center there has been a decline in the incidence of hysterectomy for life-threatening hemorrhage. Overall 83 (84.7%) patients with hysterectomy for GTN obtained remission. In patients who underwent hysterectomy to treat chemotherapy-resistant disease, 25 of 33 (75.8%) subsequently achieved complete remission. Hysterectomy continues to play an important role in the management of selected patients with GTN.


Institutional review of the management of type II odontoid fractures: associations and outcomes with fibrous union.
Type II odontoid fractures may be managed operatively or nonoperatively. If managed with bracing, bony union may never occur despite stability. This phenomenon is termed fibrous union. The authors aimed to determine associations with stable fibrous union and compare the morbidity of patients managed operatively and nonoperatively. The authors performed a retrospective review of their spine trauma database for adults with type II odontoid fractures between 2015 and 2019. Two-sample t-tests and Fisher's exact tests identified associations with follow-up stability and were used to compare operative and nonoperative outcomes. Sensitivity, specificity, and predictive values were calculated to validate initial stable upright cervical radiographs related to follow-up stability. Among 88 patients, 10% received upfront surgical fixation, and 90% were managed nonoperatively, of whom 22% had fracture instability on follow-up. Associations with instability after nonoperative management include myelopathy (OR 0.04, 95% CI 0.0-0.92), cerebrovascular disease (OR 0.23, 95% CI 0.06-1.0), and dens displacement ≥ 2 mm (OR 0.29, 95% CI 0.07-1.0). Advanced age was not associated with follow-up instability. Initial stability on upright radiographs was associated with stability on follow-up (OR 4.29, 95% CI 1.0-18) with excellent sensitivity and positive predictive value (sensitivity 89%, specificity 35%, positive predictive value 83%, and negative predictive value 46%). The overall complication rate and respiratory failure requiring ventilation on individual complication analysis were more common in operatively managed patients (33% vs 3%, respectively; p = 0.007), even though they were generally younger and healthier than those managed nonoperatively. Operative or nonoperative management conferred no difference in length of hospital or ICU stay, discharge disposition, or mortality. The authors delineate the validity of upright cervical radiographs on presentation in association with follow-up stability in type II odontoid fractures. In their experience, factors associated with instability included cervical myelopathy, cerebrovascular disease, and fracture displacement but not increased age. Operatively managed patients had higher complication rates than those managed without surgery. Fibrous union, which can occur with nonoperative management, provided adequate stability.


GW150914: Implications for the Stochastic Gravitational-Wave Background from Binary Black Holes.
The LIGO detection of the gravitational wave transient GW150914, from the inspiral and merger of two black holes with masses ≳30M_{⊙}, suggests a population of binary black holes with relatively high mass. This observation implies that the stochastic gravitational-wave background from binary black holes, created from the incoherent superposition of all the merging binaries in the Universe, could be higher than previously expected. Using the properties of GW150914, we estimate the energy density of such a background from binary black holes. In the most sensitive part of the Advanced LIGO and Advanced Virgo band for stochastic backgrounds (near 25 Hz), we predict Ω_{GW}(f=25 Hz)=1.1_{-0.9}^{+2.7}×10^{-9} with 90% confidence. This prediction is robustly demonstrated for a variety of formation scenarios with different parameters. The differences between models are small compared to the statistical uncertainty arising from the currently poorly constrained local coalescence rate. We conclude that this background is potentially measurable by the Advanced LIGO and Advanced Virgo detectors operating at their projected final sensitivity.


Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis.
The TB Vaccine Cluster project funded by the EU Fifth Framework programme aims to provide novel vaccines against tuberculosis that are suitable for evaluation in humans. This paper describes the studies of the protective efficacy of vaccines in a guinea pig aerosol-infection model of primary tuberculosis. The objective was to conduct comparative evaluations of vaccines that had previously demonstrated efficacy in other animal models. Groups of 6 guinea pigs were immunized with vaccines provided by the relevant EU Vaccine Cluster partners. Survival over 17 or 26 weeks was used as the principal measure of vaccine efficacy following aerosol challenge with H37Rv. Counts of mycobacteria in lungs and spleens, and histopathological changes in the lungs, were also used to provide evidence of protection. A total of 24 vaccines were evaluated in 4 experiments each of a different design. A heterologous prime-boost strategy of DNA and MVA, each expressing Ag85A and a fusion protein of ESAT-6 and Ag85B in adjuvant, protected the guinea pigs to the same extent as BCG. Genetically modified BCG vaccines and boosted BCG strategies also protected guinea pigs to the same extent as BCG but not statistically significantly better. A relatively high aerosol-challenge dose and evaluation over a protracted time post-challenge allowed superior protection over BCG to be demonstrated by BCG boosted with MVA and fowl pox vectors expressing Ag85A.


Diagnostic transvitreal fine-needle aspiration biopsy of small melanocytic choroidal tumors in nevus versus melanoma category.
To report an experience with fine-needle aspiration biopsy of selected small melanocytic choroidal tumors during the interval from April 13, 1983, through January 19, 2001. Retrospective descriptive case series report of 34 patients with a small melanocytic choroidal tumor (maximal diameter, < or = 10 mm; thickness, > or = 1.5 mm but < or = 3 mm) evaluated diagnostically by transvitreal fine-needle aspiration biopsy prior to treatment. None of the tumors had invasive features at the time of biopsy. Patients ranged in age from 26 to 73 years (mean, 50.9 years). The evaluated choroidal tumors had a mean maximal basal diameter of 8.0 mm and a mean maximal thickness of 2.4 mm. Eighteen of the 34 tumors (52.9%) had been documented to enlarge prior to biopsy. Biopsy was performed in all cases using a 25-gauge hollow lumen needle and a transvitreal approach via a pars plana puncture site. The biopsy yielded a sufficient aspirate for cytodiagnosis in 22 of 34 cases (64.7%). In these cases, the tumor was classified as malignant melanoma in 16 (47.1% of total), intermediate lesion in 4 (11.8%), and benign nevus in 2 (5.9%). The 12 tumors that yielded an insufficient aspirate and the four lesions that yielded intermediate cells continued to be classified as "nevus versus melanoma" and were monitored periodically for growth or other changes. Four of the 12 tumors that yielded an insufficient aspirate for cytodiagnosis and all four lesions that yielded intermediate cells were eventually reclassified as small choroidal melanomas and treated. The remaining eight tumors that yielded an insufficient aspirate and the two tumors that yielded benign nevus cells were classified as benign nevi at the most recent follow-up evaluation. Fine-needle aspiration biopsy showed that a substantial proportion of small melanocytic choroidal tumors likely to be classified clinically as small choroidal melanomas in many centers were in fact benign nevi or intermediate lesions.


The amino acid sequence of component 7c, a type II intermediate-filament protein from wool.
Component 7c is one of the four homologous type II intermediate-filament proteins that, by association with the complementary type I proteins, form the microfibrils or intermediate filaments in wool. Component 7c was isolated as the S-carboxymethyl derivative from Merino wool and its amino acid sequence was determined by manual and automatic sequencing of peptides produced by chemical and enzymic cleavage reactions. It is an N-terminally blocked molecule of 491 residues and Mr (not including the blocking group) of 55,600; the nature of the blocking group has not been determined. The predicted secondary structure shows that component 7c conforms to the now accepted pattern for intermediate-filament proteins in having a central rod-like region of approximately 310 residues of coiled-coil alpha-helix flanked by non-helical N-and C-terminal regions. The central region is divided by three non-coiled-coil linking segments into four helical segments 1A, 1B, 2A and 2B. The N-and C-terminal non-helical segments are 109 and 71 residues respectively and are rich in cysteine. Details of procedures use in determining the sequence of component 7c have been deposited as a Supplementary Publication SUP 50152 (65 pages) at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1989) 257,5. The information comprises: (1) details of chemical and enzymic methods used for cleavage of component 7c, peptides CN1, CN2 and CN3, and various other peptides, (2) details of the procedures used for the fractionation and purification of peptides from (1), including Figures showing the elution profiles from the chromatographic steps used, (3) details of methods used to determine the C-terminal sequence of peptide CN3, and (4) detailed evidence to justify a number of corrections to the previously published sequence.


Liver abscess following radioembolization with yttrium-90 microspheres.
Radioembolization with yttrium-90 microspheres is an accepted and useful intervention model with minimal invasion in both primary and secondary liver malignancies. Radioembolization may lead to some complications. Liver abscess is a rare complication that can occur several weeks after radioembolization treatment of liver tumor with yttrium-90 microspheres. There are only a few case reports on hepatic liver abscess observed in early term of radioembolization treatment, and our case also constitutes a rare report that may contribute to the possible future improvements in radioembolization field to get more insight into the current understanding of the formation of some deleterious insults such as hepatic abscess.


Artificial intelligence and deep learning in ophthalmology.
Artificial intelligence (AI) based on deep learning (DL) has sparked tremendous global interest in recent years. DL has been widely adopted in image recognition, speech recognition and natural language processing, but is only beginning to impact on healthcare. In ophthalmology, DL has been applied to fundus photographs, optical coherence tomography and visual fields, achieving robust classification performance in the detection of diabetic retinopathy and retinopathy of prematurity, the glaucoma-like disc, macular oedema and age-related macular degeneration. DL in ocular imaging may be used in conjunction with telemedicine as a possible solution to screen, diagnose and monitor major eye diseases for patients in primary care and community settings. Nonetheless, there are also potential challenges with DL application in ophthalmology, including clinical and technical challenges, explainability of the algorithm results, medicolegal issues, and physician and patient acceptance of the AI 'black-box' algorithms. DL could potentially revolutionise how ophthalmology is practised in the future. This review provides a summary of the state-of-the-art DL systems described for ophthalmic applications, potential challenges in clinical deployment and the path forward.


Positional differences in the wound transcriptome of skin and oral mucosa.
When compared to skin, oral mucosal wounds heal rapidly and with reduced scar formation. Recent studies suggest that intrinsic differences in inflammation, growth factor production, levels of stem cells, and cellular proliferation capacity may underlie the exceptional healing that occurs in oral mucosa. The current study was designed to compare the transcriptomes of oral mucosal and skin wounds in order to identify critical differences in the healing response at these two sites using an unbiased approach. Using microarray analysis, we explored the differences in gene expression in skin and oral mucosal wound healing in a murine model of paired equivalent sized wounds. Samples were examined from days 0 to 10 and spanned all stages of the wound healing process. Using unwounded matched tissue as a control, filtering identified 1,479 probe sets in skin wounds yet only 502 probe sets in mucosal wounds that were significantly differentially expressed over time. Clusters of genes that showed similar patterns of expression were also identified in each wound type. Analysis of functionally related gene expression demonstrated dramatically different reactions to injury between skin and mucosal wounds. To explore whether site-specific differences might be derived from intrinsic differences in cellular responses at each site, we compared the response of isolated epithelial cells from skin and oral mucosa to a defined in vitro stimulus. When cytokine levels were measured, epithelial cells from skin produced significantly higher amounts of proinflammatory cytokines than cells from oral mucosa. The results provide the first detailed molecular profile of the site-specific differences in the genetic response to injury in mucosa and skin, and suggest the divergent reactions to injury may derive from intrinsic differences in the cellular responses at each site.


Optic flow detection is not influenced by visual-vestibular congruency.
Optic flow patterns generated by self-motion relative to the stationary environment result in congruent visual-vestibular self-motion signals. Incongruent signals can arise due to object motion, vestibular dysfunction, or artificial stimulation, which are less common. Hence, we are predominantly exposed to congruent rather than incongruent visual-vestibular stimulation. If the brain takes advantage of this probabilistic association, we expect observers to be more sensitive to visual optic flow that is congruent with ongoing vestibular stimulation. We tested this expectation by measuring the motion coherence threshold, which is the percentage of signal versus noise dots, necessary to detect an optic flow pattern. Observers seated on a hexapod motion platform in front of a screen experienced two sequential intervals. One interval contained optic flow with a given motion coherence and the other contained noise dots only. Observers had to indicate which interval contained the optic flow pattern. The motion coherence threshold was measured for detection of laminar and radial optic flow during leftward/rightward and fore/aft linear self-motion, respectively. We observed no dependence of coherence thresholds on vestibular congruency for either radial or laminar optic flow. Prior studies using similar methods reported both decreases and increases in coherence thresholds in response to congruent vestibular stimulation; our results do not confirm either of these prior reports. While methodological differences may explain the diversity of results, another possibility is that motion coherence thresholds are mediated by neural populations that are either not modulated by vestibular stimulation or that are modulated in a manner that does not depend on congruency.


[Reversion of the immunological eclipse and therapeutic vaccination against cancer in an experimental model].
Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the antitumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors.


Phototriggered functionalization of hierarchically structured polymer brushes.
The precise design of bioactive surfaces, essential for the advancement of many biomedical applications, depends on achieving control of the surface architecture as well as on the ability to attach bioreceptors to antifouling surfaces. Herein, we report a facile avenue toward hierarchically structured antifouling polymer brushes of oligo(ethylene glycol) methacrylates via surface-initiated atom transfer radical polymerization (SI-ATRP) presenting photoactive tetrazole moieties, which permitted their functionalization via nitrile imine-mediated tetrazole-ene cyclocloaddition (NITEC). A maleimide-functional ATRP initiator was photoclicked to the side chains of a brush enabling a subsequent polymerization of carboxybetaine acrylamide to generate a micropatterned graft-on-graft polymer architecture as evidenced by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Furthermore, the spatially resolved biofunctionalization of the tetrazole-presenting brushes was accessed by the photoligation of biotin-maleimide and subsequent binding of streptavidin. The functionalized brushes bearing streptavidin were able to resist the fouling from blood plasma (90% reduction with respect to bare gold). Moreover, they were employed to demonstrate a model biosensor by immobilization of a biotinylated antibody and subsequent capture of an antigen as monitored in real time by surface plasmon resonance.


Inter- and Intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery.
The continued refinement of non-invasive brain stimulation (NBS) techniques is indicative of promising clinical and rehabilitative interventions that are able to modulate cortical excitability. Intermittent theta burst stimulation (iTBS) is one such technique that can increase cortical excitability, purportedly via LTP-like mechanisms. While iTBS may have the capacity to promote recovery after neurological injury, and to combat cognitive and motor decline, recent reports observed highly variable effects across individuals, questioning the efficacy of iTBS as a clinical tool. The aim of this study was to examine intra-individual reliability and inter-individual variability in responses to iTBS. Thirty healthy participants completed two experimental sessions of the iTBS protocol 1-3 weeks apart. Motor evoked potentials in response to single pulse TMS were used to assess corticospinal excitability prior to, and up to 36 min following, iTBS. At the group level, iTBS evoked statistically significant increases in motor cortical excitability across both sessions (P < 0.001), with 22 out of 30 participants exhibiting increases in excitability in both sessions. A strong intraclass correlation demonstrated that both the direction, and magnitude of the plastic changes were reliable at the individual level. Overall, our results suggest that iTBS is capable of inducing relatively robust and consistent effects within and between young individuals. As such, the capacity for iTBS to be exploited in clinical and rehabilitative interventions should continue to be explored.


Novel homozygous splicing mutations in ARL2BP cause autosomal recessive retinitis pigmentosa.
Mutations in ARL2BP, encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases associated with ARL2BP variants. Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in 1,051 unrelated individuals recruited for the UK Inherited Retinal Disease Consortium and NIHR-BioResource Rare Diseases research studies. Sanger sequencing was used to validate the next-generation sequencing data, and reverse transcriptase (RT)-PCR analysis was performed on RNA extracted from blood from affected individuals to test for altered splicing of ARL2BP. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography. Homozygous variants in ARL2BP (NM_012106.3) were identified in two unrelated individuals with RP. The variants, c.207+1G>A and c.390+5G>A, at conserved splice donor sites for intron 3 and intron 5, respectively, were predicted to alter the pre-mRNA splicing of ARL2BP. RT-PCR spanning the affected introns revealed that both variants caused abnormal splicing of ARL2BP in samples from affected individuals. This study identified two homozygous variants in ARL2BP as a rare cause of arRP. Further studies are required to define the underlying disease mechanism causing retinal degeneration as a result of mutations in ARL2BP and any phenotype-genotype correlation associated with residual levels of the wild-type transcript.


Light-sheet microscopy for everyone? Experience of building an OpenSPIM to study flatworm development.
Selective plane illumination microscopy (SPIM a type of light-sheet microscopy) involves focusing a thin sheet of laser light through a specimen at right angles to the objective lens. As only the thin section of the specimen at the focal plane of the lens is illuminated, out of focus light is naturally absent and toxicity due to light (phototoxicity) is greatly reduced enabling longer term live imaging. OpenSPIM is an open access platform (Pitrone et al. 2013 and OpenSPIM.org) created to give new users step-by-step instructions on building a basic configuration of a SPIM microscope, which can in principle be adapted and upgraded to each laboratory's own requirements and budget. Here we describe our own experience with the process of designing, building, configuring and using an OpenSPIM for our research into the early development of the polyclad flatworm Maritigrella crozieri - a non-model animal. Our OpenSPIM builds on the standard design with the addition of two colour laser illumination for simultaneous detection of two probes/molecules and dual sided illumination, which provides more even signal intensity across a specimen. Our OpenSPIM provides high resolution 3d images and time lapse recordings, and we demonstrate the use of two colour lasers and the benefits of two color dual-sided imaging. We used our microscope to study the development of the embryo of the polyclad flatworm M. crozieri. The capabilities of our microscope are demonstrated by our ability to record the stereotypical spiral cleavage pattern of M. crozieri with high-speed multi-view time lapse imaging. 3D and 4D (3D + time) reconstruction of early development from these data is possible using image registration and deconvolution tools provided as part of the open source Fiji platform. We discuss our findings on the pros and cons of a self built microscope. We conclude that home-built microscopes, such as an OpenSPIM, together with the available open source software, such as MicroManager and Fiji, make SPIM accessible to anyone interested in having continuous access to their own light-sheet microscope. However, building an OpenSPIM is not without challenges and an open access microscope is a worthwhile, if significant, investment of time and money. Multi-view 4D microscopy is more challenging than we had expected. We hope that our experience gained during this project will help future OpenSPIM users with similar ambitions.


Ryanodine and inositol trisphosphate receptors are differentially distributed and expressed in rat parotid gland.
The present study examines the cellular distribution of the ryanodine receptor/channel (RyR) and inositol 1,4,5-trisphosphate receptor (InsP3R) subtypes in parotid acini. Using fluorescently labelled 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-3-propionic acid glycyl-ryanodine (BODIPYtrade mark-ryanodine) and confocal microscopy, RyRs were localized primarily to the perinuclear region (basal pole) of the acinar cell. Ryanodine, Ruthenium Red, cAMP and cADP ribose (cADPR) competed with BODIPY-ryanodine, resulting in a reduction in the fluorescence signal. However, inositol 1,4, 5-trisphosphate [Ins(1,4,5)P3] did not alter the binding of BODIPY-ryanodine. Using receptor-subtype-specific antisera, InsP3Rs (types I, II and III) were located predominantly in the apical pole of the parotid cell. The presence of these three subtypes was confirmed using reverse transcriptase PCR with RNA-specific oligonucleotide probes. Binding studies using a parotid cell-membrane fraction identified and characterized RyRs and InsP3Rs in terms of binding affinity (Kd) and maximum binding capacity (Bmax) and confirmed that cADPR displaces ryanodine from its binding sites. Ruthenium Red and 8-Br-cADP-ribose blocked Ca2+ release in permeabilized acinar cells in response to cADPR and cAMP or forskolin, whereas Ins(1,4,5)P3-induced Ca2+ release was unaffected. The localization of the RyRs and InsP3Rs in discrete regions endow broad areas of the parotid cell with ligand-activated Ca2+ channels. The consequences of the dual activation of the RyRs and InsP3Rs by physiologically relevant stimuli such as noradrenaline (norepinephrine) are considered in relation to Ca2+ signalling in the parotid gland.


Selective DNAzyme-mediated cleavage of AChR mutant transcripts by targeting the mutation site or through mismatches in the binding arm.
Many dominantly inherited disorders are caused by missense amino acid substitutions resulting from a single nucleotide exchange in the encoding gene. For these disorders, where proteins expressed from the mutant alleles are often pathogenic and present throughout life, gene silencing, through intervention at the mRNA level, holds promise as a therapeutic approach. We have used mutations that underlie the slow channel congenital myasthenic syndrome (SCCMS) as a model system to study allele-specific gene silencing of RNA transcripts by DNAzymes. We tested the ability of DNAzymes to give allele-specific cleavage for i) mutations that create cleavage sites, and ii) mutations located close to a DNAzyme cleavage site that create a potential mismatch in the binding arms. For both we demonstrate selective cleavage of mutant transcripts under simulated physiological conditions. For DNAzymes with binding arm mismatches the degree of selectivity for mutant over wild type may be enhanced by optimising the mismatch position as well as the binding arm length. The optimal sites for mismatches are 1.1 and 1.2 in arm I, and 16.2 in arm II. Asymmetric binding arm DNAzymes with a shorter arm I are more discriminative. Our results show it should be possible to apply DNAzyme-mediated cleavage of mutant alleles even when the mutant does not itself create a putative cleavage site. This therapeutic approach may be well suited to dominantly inherited disorders such as SCCMS, where loss of some wild type transcripts is unlikely to have pathogenic consequences.


Arabidopsis thaliana sku mutant seedlings show exaggerated surface-dependent alteration in root growth vector.
Roots of wild-type Arabidopsis thaliana seedlings in the Wassilewskija (WS) and Landsberg erecta (Ler) ecotypes often grow aslant on vertical agar surfaces. Slanted root growth always occurs to the right of the gravity vector when the root is viewed through the agar surface, and is not observed in the Columbia ecotype. Right-slanted root growth is surface-dependent and does not result directly from directional environmental stimuli or gradients in the plane of skewing. We have isolated two partially dominant mutations in WS (sku1 and sku2) that show an exaggerated right-slanting root-growth phenotype on agar surfaces. The right-slanting root-growth phenotype of wild-type and mutant roots is not the result of diagravitropism or of an alteration in root gravitropism. It is accompanied by a left-handed rotation of the root about its axis within the elongation zone, the rate of which positively correlates with the degree of right-slanted curvature. Our data suggest that the right-slanting root growth phenotype results from an endogenous structural asymmetry that expresses itself by a directional root-tip rotation.


Long-term domiciliary oxygen in chronic bronchitis with pulmonary hypertension.
Five patients with chronic bronchitis and pulmonary hypertension were treated with oxygen in their homes for periods of between 6 and 24 months. Oxygen was supplied for 15 hours daily from cylinders or from an oxygen concentrator and few practical difficulties arose. After 23 to 59 weeks of treatment there were significant decreases in pulmonary arterial pressure and vascular resistance, and four of the five patients no longer had pulmonary hypertension at rest. Two of these patients had shown little response after three weeks of treatment. There was a reduction in the number of episodes of congestive cardiac failure compared with the corresponding period before treatment. Two of the patients improved enough to return to work. These results are encouraging enough to justify a controlled trial of the treatment in a large number of patients.


Impaired effectiveness of nitric oxide-donors in resistance arteries of patients with arterial hypertension.
To assess the dilatory effectiveness of nitric oxide donors in resistance arteries of patients with arterial hypertension in comparison with that in those of normotensive controls. Endothelium-dependent vasodilation has been demonstrated to be impaired in arterial hypertension. Besides disturbances in endothelial nitric oxide production a reduced vasodilatory effectiveness of nitric oxide might contribute to this phenomenon of endothelial dysfunction. We therefore investigated the dilatory responsiveness of resistance arteries to exogenous nitric oxide by means of administration of the nitric oxide donors glycerol trinitrate (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (SNP) in hypertensive patients. Forearm blood flow was measured by venous occlusion plethysmography at rest and during intra-arterial infusion of nitric oxide donors at increasing doses in 11 patients with arterial hypertension and in 10 age-matched normotensive controls. Forearm blood flow at rest was comparable in the two groups and was dose-dependently increased by administration of either nitric oxide donor. In patients with arterial hypertension, blood flow responses to infusions of organic nitrates were significantly impaired over the entire dose-response curve compared with those of normotensive controls (220 nmol/min GTN 13.1 +/- 1.3 and 8.6 +/- 0.3 ml/min per 100 ml tissue; 212 nmol/min ISDN 9.9 +/- 0.7 and 5.8 +/- 1.0 ml/min per 100 ml tissue). Blood flow responses to infusion of the nitric oxide donor SNP were also profoundly impaired in the hypertensive patients, the extent of which impairment equalled that found with the organic nitrates. Within the entire set of normotensive and hypertensive subjects, maximal flow responses to either nitric oxide donor were inversely correlated with mean arterial blood pressure. Dilation of resistance arteries in response to infusion of nitric oxide donors is impaired in hypertensive patients and the degree of this impairment depends critically on the severity of arterial hypertension. The reduced effectiveness of nitric oxide appears to be independent of the class of nitric oxide donor and thus of the mode of intravascular nitric oxide generation. These findings are likely to have important implications not only for our understanding of the pathophysiological mechanisms of endothelial dysfunction but also for nitric oxide donor therapy in arterial hypertension.


Towards defect-free 1-D GaAs/AlGaAs heterostructures based on GaAs nanomembranes.
We demonstrate the growth of defect-free zinc-blende GaAs nanomembranes by molecular beam epitaxy. Our growth studies indicate a strong impact of As4 re-emission and shadowing in the growth rate of the structures. The highest aspect ratio structures are obtained for pitches around 0.7-1 μm and a gallium rate of 1 Å s(-1). The functionality of the membranes is further illustrated by the growth of quantum heterostructures (such as quantum wells) and the characterization of their optical properties at the nanoscale. This proves the potential of nanoscale membranes for optoelectronic applications.


Early eocene bat from wyoming.
A fossil skeleton of an early Eocene bat, the oldest known flying mammal, was found in southwest Wyoming. The bat is assigned to the new species Icaronycteris index of the suborder Microchiroptera. It was apparently of a young male whose body was buried in varved marls of the Green River Formation, on the bottom of Fossil Lake, about 50 million years ago. The bones, some as slender as a human hair, show a few "primitive" characteristics such as a clawed index finger and a complete phalangeal formula, but the bat was fully developed -an anatomically precocious contemporary of the dog-sized polydactylous horse.


Papio Cranium from the Hominin-Bearing Site of Malapa: Implications for the Evolution of Modern Baboon Cranial Morphology and South African Plio-Pleistocene Biochronology.
A new partial cranium (UW 88-886) of the Plio-Pleistocene baboon Papio angusticeps from Malapa is identified, described and discussed. UW 88-886 represents the only non-hominin primate yet recovered from Malapa and is important both in the context of baboon evolution as well as South African hominin site biochronology. The new specimen may represent the first appearance of modern baboon anatomy and coincides almost perfectly with molecular divergence date estimates for the origin of the modern P. hamadryas radiation. The fact that the Malapa specimen is dated between ~2.026-2.36 million years ago (Ma) also has implications for the biochronology of other South African Plio-Pleistocene sites where P. angusticeps is found.


Obesity and mortality after breast cancer by race/ethnicity: The California Breast Cancer Survivorship Consortium.
We investigated body size and survival by race/ethnicity in 11,351 breast cancer patients diagnosed from 1993 to 2007 with follow-up through 2009 by using data from questionnaires and the California Cancer Registry. We calculated hazard ratios and 95% confidence intervals from multivariable Cox proportional hazard model-estimated associations of body size (body mass index (BMI) (weight (kg)/height (m)(2)) and waist-hip ratio (WHR)) with breast cancer-specific and all-cause mortality. Among 2,744 ascertained deaths, 1,445 were related to breast cancer. Being underweight (BMI <18.5) was associated with increased risk of breast cancer mortality compared with being normal weight in non-Latina whites (hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.14, 3.20), whereas morbid obesity (BMI ≥ 40) was suggestive of increased risk (HR = 1.43, 95% CI: 0.84, 2.43). In Latinas, only the morbidly obese were at high risk of death (HR = 2.26, 95% CI: 1.23, 4.15). No BMI-mortality associations were apparent in African Americans and Asian Americans. High WHR (quartile 4 vs. quartile 1) was associated with breast cancer mortality in Asian Americans (HR = 2.21, 95% CI: 1.21, 4.03; P for trend = 0.01), whereas no associations were found in African Americans, Latinas, or non-Latina whites. For all-cause mortality, even stronger BMI and WHR associations were observed. The impact of obesity and body fat distribution on breast cancer patients' risk of death may vary across racial/ethnic groups.


Application of leaching tests on phosphogypsum by infiltration-percolation.
The phosphoric acid production obtained by attacking phosphate rock by sulphuric acid cogenerates considerable quantities of phosphogypsum. The world cogeneration is estimated about 100-280 Mt per year. In another context of sustainable development, the phosphate chemical industry develops different ways of phosphogypsum valorization, which makes its storage stack in a suitable way for its potential use as an industrial by-product. Although, this storage can cause an environmental impact largely due to the transfer of trace elements (TEs) to groundwater by leaching. It is therefore important to evaluate the impact linked to the storage in order to limit this transfer. The evaluation is usually performed through leaching tests in columns or reactor. In this work, leaching tests were performed in columns by infiltration-percolation on two filter mediums: phosphogypsum and synthetic sandy soils. The results showed that the phosphogypsum is acting as a filter, which retains and releases the TEs. Most of these TEs (Pb, Se, Ag, Zn and Cu) were highly retained in the synthetic soils surfaces and their contents in waters were considerably lower than the maximum contaminant levels (MCLs). Although As, Cd, Cr and Ni were strongly transferred to groundwater, their respective contents were higher than the MCLs.


Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee.
Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation. The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values ≥3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24 hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48 hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP. This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP.


Mixed muscle and hepatic derived plasma protein metabolism is differentially regulated in older and younger men following resistance exercise.
We sought to determine whether exercise-induced muscle protein turnover alters the subsequent production of hepatically derived acute-phase plasma proteins, and whether age affects how these proteins are regulated. We measured arteriovenous (a-v) balance and the synthesis of mixed muscle protein, albumin (A) and fibrinogen (F) before exercise (REST) and from the beginning of exercise to 10, 60, and 180 min following a single bout of moderate-intensity leg extension exercise (POST-EX) in postabsorptive untrained older (n = 6) and younger (n = 6) men using L-[ring-2H5]phenylalanine (Phe). Subjects performed 6 sets of 8 repetitions of leg extension at 80% of their 1-RM (one-repetition maximum). All data are presented as the difference from REST (Delta from REST at 10, 60, and 180 min POST-EX). Mixed muscle fractional synthesis rate (FSR-M) increased significantly from the beginning of exercise until 10 min POST-EX in the older men (DeltaFSR-M: 0.044%/h), whereas FSR-M in the younger men was not elevated until 180 min POST-EX (DeltaFSR-M: 0.030%/h). FSR-A and FSR-F increased at all POST-EX periods in the older men (DeltaFSR-A = 10 min: 1.90%/day; 60 min: 2.72%/day; 180 min: 2.78%/day; DeltaFSR-F = 10 min: 1.00%/day; 60 min: 3.01%/day; 180 min: 3.73%/day). No change occurred in FSR-A in the younger men, but FSR-F was elevated from the beginning of exercise until 10 and 180 min POST-EX (10 min: 3.07%/day and 180 min: 3.96%/day). Net balance of Phe was positive in the older men in the immediate POST-EX period. Our data indicate that mixed muscle and hepatic derived protein synthesis is differentially regulated in younger and older men in response to a single bout of moderate-intensity leg extension exercise. Moreover, our data suggest that with age may come a greater need to salvage or make available amino acids from exercise-induced muscle protein breakdown to mount an acute-phase response.


Blockade Effects of Anti-Interferon- (IFN-) γ Autoantibodies on IFN-γ-Regulated Antimicrobial Immunity.
The interferon- (IFN-) γ expression is elicited in response to microbial infections and activates immune surveillance by antimicrobial immune elements to induce microbial killing. Patients with adult-onset immunodeficiency who suffer from recurrent infections with microbes, particularly nontuberculous mycobacteria (NTM), commonly display genetic defects in IFN-γ signaling as well as the generation of anti-IFN-γ autoantibodies (autoAbs). Because IFN-γ is an activator of macrophage differentiation and a proinflammatory activator of innate immunity, the blockade effects of the autoAbs present in NTM patient serum on IFN-γ are hypothesized to regulate the antimicrobial function of macrophages. In the presence of patient serum, IFN-γ-induced type 1 macrophage (M1) differentiation was inhibited in PMA-stimulated human monocytic THP-1 cells. Treatment with patient serum significantly blocked the production of proinflammatory factors, including cytokines/chemokines and reactive oxygen/nitrogen species, by M1 macrophages. Importantly, IFN-γ-facilitated phagocytosis and degradation of heat-killed mycobacterium were decreased by cotreatment with patient serum. These results show the blockade activity of anti-IFN-γ autoAbs on IFN-γ-mediated antimicrobial immunity in macrophages.


Store type and demographic influence on the availability and price of healthful foods, Leon County, Florida, 2008.
The availability of healthful foods varies by neighborhood. We examined the availability and price of more healthful foods by store type, neighborhood income level, and racial composition in a community with high rates of diet-related illness and death. We used the modified Nutrition Environment Measures Survey in Stores to conduct this cross-sectional study in 2008. We surveyed 73 stores (29% supermarkets, 11% grocery stores, and 60% convenience stores) in Leon County, Florida. We analyzed the price and availability of foods defined by the 2005 Dietary Guidelines for Americans as "food groups to encourage." We used descriptive statistics, t tests, analysis of variance, and χ(2) tests in the analysis. Measures of availability for all more healthful foods differed by store type (P < .001). Overall, supermarkets provided the lowest price for most fresh fruits and vegetables, low-fat milk, and whole-wheat bread. Availability of 10 of the 20 fruits and vegetables surveyed, shelf space devoted to low-fat milk, and varieties of whole-wheat bread differed by neighborhood income level (P < .05), but no trends were seen for the availability or price of more healthful foods by neighborhood racial composition. Store type affects the availability and price of more healthful foods. In particular, people without access to supermarkets may have limited ability to purchase healthful foods. Nutrition environment studies such as this one can be used to encourage improvements in neighborhoods that lack adequate access to affordable, healthful food, such as advocating for large retail stores, farmer's markets, and community gardens in disadvantaged neighborhoods.


An oscillatory current in sheep cardiac Purkinje fibers.
The inward current ("oscillatory current") which may be present after the end of a depolarizing clamp was studied in sheep cardiac Purkinje fibers by means of a voltage-clamp method. The following results were obtained. In order to appear, the oscillatory current (Ios) requires a previous depolarization to approximately or equal to -20 mV or beyond and a repolarization to approximately or equal to -40 mV or to more negative potentials. The Ios requires a minimum duration of the depolarizing clamp and becomes larger with longer clamps. With repolarization to more negative potentials (approximately or equal to 90 mV), Ios becomes smaller and may disappear. Also Ios can be triggered twice if the potential is clamped to two different levels in succession. By several procedures which modify the other known currents (fast Na+ current, slow inward current, early outward current, plateau current Ix1 and pacemaker current), it can be demonstrated that Ios is not due to their oscillatory behavior and can occur in the absence of any one of them. Interventions which increase the contractile force presumably by increasing intracellular calcium stores enhance the Ios or may make it appear. In fact, these interventions may extend the voltage range over which Ios appears. These interventions include lowering potassium, increasing calcium, trains of depolarizing clamps, and administration of norepinephrine and of strophanthidin. It is concluded that Ios is a physiological event which is enhanced by certain procedures, and it appears to be of much importance in drive-induced arrhythmias under different conditions.


Mortality among United Kingdom servicemen who served abroad in the 1950s and 1960s.
The Registrar General's decennial supplements on occupational mortality provide only limited information on mortality in the armed forces in the United Kingdom. Mortality has therefore been studied among a group of 30,619 United Kingdom servicemen who served abroad in tropical or desert areas in the 1950s and 1960s, and who remained in the services for a total of at least five years. Mortality from all causes of death, all neoplasms, and all other known non-violent causes was lower than that expected from rates for all men in England and Wales, whereas mortality from accidents and violence was raised. These differences remained after adjustment for social class, affected both officers and other ranks, and had not disappeared even after the men had been followed up for at least 20 years. When mortality from 20 specific cancers and 10 other disease groups was examined there were significant excesses for cancers of the oesophagus (standardised mortality ratio (SMR) = 146; p = 0.03) and prostate (SMR = 156; p = 0.03), and significant deficits for cancers of the lung (SMR = 73; p less than 0.001), stomach (SMR = 66; p = 0.002), bladder (SMR = 53; p = 0.02), other specified neoplasms (SMR = 48; p = 0.001), coronary heart disease (SMR = 76; p less than 0.001), bronchitis, emphysema, and chronic obstructive lung disease (SMR = 42; p less than 0.001), and for five further groups of diseases unrelated to smoking or alcohol. Examination of mortality in each of the three services separately identified two specific hazards in the Royal Navy; seven deaths from mesothelioma occurred compared with less than 2.06 expected (p less than 0.005), and there was also an excess of neoplasms and of other diseases associated with alcohol (SMRs of 181 and 229; p = 0.002 and less than 0.001). Mortality from smoking related diseases other than those associated with alcohol was low in all three services, particularly among officers.


Cholesterol paradox in patients with paroxysmal atrial fibrillation.
Hypercholesterolemia is a major risk factor for coronary heart disease (CHD), but the associations among lipids, lipoproteins and paroxysmal atrial fibrillation (PAF) have not yet been reported. The associations among lipids, lipoproteins and PAF were examined in a case-control study, in which cases and controls were defined as those with/without definite ECG-detectable PAF, respectively. CHD patients were excluded from the study. The mean values of serum total cholesterol (TC), triglyceride (TG) and high density lipoprotein-cholesterol (HDL-C), after adjusting for age and gender, in patients with PAF were lower than those in patients without PAF (175 +/- 4 mg/dl vs. 190 +/- 3 mg/dl, 104 +/- 7 mg/dl vs. 123 +/- 6 mg/dl, 46.0 +/- 1.7 mg/dl vs. 51.8 +/- 1.4 mg/dl, respectively), as assessed by an analysis of covariance. After controlling for age and gender, TC, TG and HDL-C (all in quartiles) were inversely and linearly (p < 0.05) associated with the percentage of patients with PAF, as assessed by a multiple logistic regression analysis. The associations between TC or TG and PAF varied with the HDL-C level: significant when HDL-C was low (p < 0.05), but not when HDL-C was high. The odds ratio (relative risk of PAF) for patients with both low TC or TG and low HDL-C was 4.08 (95% CI: 1.81-9.57) times or 9. 40 (3.25-32.0) times higher (p < 0.01) than that for patients with high TC or TG and high HDL-C, respectively. In conclusion, low serum levels of TC and TG were found in PAF patients, while reduced HDL-C may cause PAF. Hypolipoproteinemia including low HDL-C may affect atrial vulnerability and cause atrial fibrillation.


Calcium- and mucin-binding proteins of staphylococci.
The association of staphylococci with the mucus gel that overlays the mucosa of the respiratory tract may lead to clearance of cocci or, in certain conditions such as cystic fibrosis (CF), to colonization. In the present study, a quantitative radioassay was used to study the effect of Ca2+, which is elevated in CF sputa, on the adhesion of 3H-labelled Staphylococcus aureus to submaxillary gland mucin immobilized in MaxiSorp 96-well, break-apart modules. Ca2+ significantly enhanced the adhesion of S. aureus (five strains) and Staphylococcus epidermidis (four strains). The reaction was specific because adhesion was not enhanced in the presence of Mg2+, Ca(2+) + EGTA (a Ca2+ chelator) or protamine and was not attributable to hydrophobicity of the test strains. Staphylococcal adhesion was significantly (P < or = 0.005) blocked in the presence of highly sialated and sulphated reagents, which suggests that Ca2+ binds to the sialic acid and sulphate residues of immobilized mucin. The Ca(2+)-binding sites on the surface of S. aureus were trypsin-sensitive; in addition, 125I-labelled solubilized S. aureus surface proteins reacted with immobilized mucin in a direct binding assay, and the reaction was significantly enhanced by Ca2+. Autoradiography demonstrated that 45Ca bound directly to two polypeptides (M(r) 170,000 and 150,000) of solubilized staphylococcal surface proteins separated by SDS-PAGE, and that 125I-labelled mucin bound directly to three staphylococcal polypeptides (M(r) 40,000, 35,000, and 29,000). These results suggest that S. aureus adhesion to mucin is mediated by at least two mechanisms: via Ca(2+)-binding surface proteins in the presence of Ca2+ and via mucin-binding surface proteins unrelated to Ca2+.


Gene 4 protein of bacteriophage T7. Characterization of the product synthesized by the T7 DNA polymerase and gene 4 protein in the absence of ribonucleoside 5'-triphosphates.
DNA polymerase and gene 4 protein of bacteriophage T7 catalyze extensive DNA synthesis on duplex phage T7 or PM2 DNA templates containing single strand breaks. A variety of physicochemical techniques have been used to characterize the DNA product synthesized in this reaction in the absence of ribonucleoside 5'-triphosphates. Pyknographic and sedimentation analyses reveal that all of the newly synthesized DNA is covalently attached to the template DNA. Analysis by electron microscopy shows the major portion of the product molecules synthesized on duplex T7 DNA templates to consist of a double-stranded branch attached to an intact template molecule. Using PM2 DNA templates, the predominant product consists of a double-stranded branch attached to the circular PM2 DNA template. Analyses of these product molecules indicate that DNA synthesis by the gene 4 protein and T7 DNA polymerase is initiated at single strand breaks in the duplex DNA and that synthesis is accompanied by extensive displacement of one of the parental strands. At later times in the reaction, a portion of the 3'-hydroxyl terminus of the newly synthesized DNA is displaced from the template by branch migration and is used as a primer by the DNA polymerase to copy the displaced 5' single-stranded parental strand to form a duplex branch.


Impact of tumor sidedness on survival and recurrence patterns in colon cancer patients.
Previous studies have reported conflicting results regarding the prognostic value of tumor sidedness in colon cancer. We investigated the oncologic impact of tumor location and examined whether recurrence patterns were related to tumor sidedness in colon cancer patients. We identified stage I-III colon adenocarcinoma patients from a prospective colorectal cancer registry at Severance Hospital, Seoul, Korea, who underwent complete mesocolic excision between 2005 and 2012. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for predictors of cancer-specific survival (CSS), recurrence-free survival (RFS), and cumulative recurrence at specific anatomic sites were examined using Cox proportional hazard regression analysis. Overall, 1,912 patients, 1,077 (56.3%) with left-sided colon cancer (LCC), and 835 (43.7%) with right-sided colon cancer (RCC), at a median follow-up of 59 months, were eligible and included in the study. In univariate analysis, similar 5-year CSS and RFS were observed for LCC and RCC in the total patient population, and when stratified by stage for stage I and II patients. For stage III patients, an adjusted Cox regression analysis indicated that RCC patients had a higher risk of cancer-specific mortality (HR, 1.75; 95% CI, 1.07-2.86; P = 0.024) and recurrence (HR, 1.78; 95% CI, 1.22-2.60; P = 0.003). Furthermore, RCC was an independent predictor of peritoneal recurrence (HR, 1.86; 95% CI, 1.05-3.29; P = 0.031) in stage III patients. RCC correlated with worse CSS and RFS than LCC. In stage III patients, RCC correlated with increased risk of peritoneal recurrence. The reasons for these differences remain to be investigated.


COVID-19 pandemic and psychological fatigue in Turkey.
The aim of this study was to investigate the association between the COVID-19 pandemic and psychological fatigue as a mental health issue among the population of Istanbul, Turkey. This is a cross-sectional study conducted in Istanbul, Turkey, between March and June 2020, where a total of 4,700 persons were approached and 3,672 (78%) of participants (64.4% males and 35.6% females) completed the Knowledge Attitude Practices (KAP) and Fatigue Assessment Scale (FAS) questionnaires. In this study, 64.1% of participants were categorized as psychologically fatigued and 35.9% as normal. There was a significant difference between fatigued and normal participants with respect to age, educational level, occupational status, place of residence and number of family members (p < .001). Other differences related to knowledge of COVID-19 were symptoms, treatment, ways of spreading (p < .001), prevention by avoiding crowded places (p = .008) and isolation (p = .002). For attitudinal items, normal participants generally showed more positive attitudes than the fatigued in believing that COVID-19 will finally be controlled, satisfaction with preventive measures taken by the authorities, reporting suspected cases with symptoms and trusting that Turkey can overcome the COVID-19 pandemic (p < .001). Multivariate stepwise regression analysis indicated that level of education, avoiding going to crowded places, eye, nose and mouth organs are sensitive organs to the virus, keeping physical distance due to epidemic affect by COVID-19 virus, isolation and treatment of people reduce the spread of COVID-19 virus and 14-days period of time, COVID-19 is mainly transmitted through contact with the respiratory droplets of an infected person, occupational status, health education programme needed and antibody treatment variables were significantly associated with fatigue after adjusting for age, gender and income variables. The current study provides valuable information for policymakers and mental health professionals worldwide regarding associations between the mental health of individuals and the ongoing outbreak, COVİD-19.


In vivo cell reprogramming towards pluripotency by virus-free overexpression of defined factors.
The ability to induce the reprogramming of somatic mammalian cells to a pluripotent state by the forced expression of specific transcription factors has helped redefine the rules of cell fate and plasticity, as well as open possibilities for disease modeling, drug screening and regenerative medicine. Here, we hypothesized that the non-viral forced expression of the four originally discovered defined factors (OKSM) in adult mice could result in in vivo reprogramming of cells in the transfected tissue in situ. We show that a single hydrodynamic tail-vein (HTV) injection of two plasmids encoding for Oct3/4, Sox2, Klf4 and c-Myc respectively, are highly expressed in the liver tissue of Balb/C adult mice. Hallmark pluripotency markers were upregulated within 24-48 h after injection, followed by down-regulation of all major hepatocellular markers. Generation of transcriptionally reprogrammed cells in vivo was further confirmed by positive staining of liver tissue sections for all major pluripotency markers in Balb/C mice and the Nanog-GFP reporter transgenic strain (TNG-A) with concomitant upregulation of GFP expression in situ. No signs of physiological or anatomical abnormalities or teratoma formation were observed in the liver examined up to 120 days. These findings indicate that virus-free expression of OKSM factors in vivo can transcriptionally reprogram cells in situ rapidly, efficiently and transiently, absent of host tissue damage or teratoma formation.


HPR1 encodes a global positive regulator of transcription in Saccharomyces cerevisiae.
The Hpr1 protein has an unknown function, although it contains a region of homology to DNA topoisomerase I. We have found that hpr1 null mutants are defective in the transcription of many physiologically unrelated genes, including GAL1, HO, ADH1, and SUC2, by using a combination of Northern (RNA) blot analysis, primer extension, and upstream activation sequence-lacZ fusions. Many of the genes positively regulated by HPR1 also require SWI1, SWI2-SNF2, SWI3, SNF5, and SNF6. The transcriptional defect at HO and the CCB::lacZ upstream activation sequence in hpr1 mutants is partially suppressed by a deletion of SIN1, which encodes an HMG1p-like protein. Elevated gene dosage of either histones H3 and H4 or H2A and H2B results in a severe growth defect in combination with an hpr1 null mutation. However, increased gene dosage of all four histones simultaneously restores near-normal growth in hpr1 mutants. Altered in vivo Dam methylase sensitivity is observed at two HPR1-dependent promoters (GAL1 and SUC2). Most of the Hpr1 protein present in the cell is in a large complex (10(6) Da) that is distinct from the SWI-SNF protein complex. We propose that HPR1 affects transcription and recombination by altering chromatin structure.


Time trends and demographics of deaths from congenital hydrocephalus in children in the United States: National Center for Health Statistics data, 1979 to 1998.
Congenital hydrocephalus has an estimated population incidence of 0.2 to 0.8/1000 live births. With improvements in techniques for cerebrospinal fluid shunting, treatment of hydrocephalus has become safe and routine, yet data describing mortality from congenital hydrocephalus or demonstrating improvements in mortality with the advent of modern treatment are scarce. The authors' analysis sought to rectify this situation. The authors performed an electronic search of National Center for Health Statistics death certificate databases to identify deaths from 1979 to 1998 attributed to congenital hydrocephalus, spina bifida with hydrocephalus, and acquired hydrocephalus (both obstructive and communicating) in all children in the US aged 1 day to 20 years. Mortality rates were defined as deaths per 100,000 person-years and were analyzed for differences on the basis of age, race, sex, and year. The authors identified 10,406 deaths attributed to childhood hydrocephalus within the 20-year study period. The overall mortality rate was 0.71 per 100,00 person-years. Mortality rates were highest in infants, with 3979 deaths; they were similar between girls and boys. Compared with white infants, black infants had higher relative risk (RR) for death caused by congenital hydrocephalus (RR 1.46, p value < 0.0001) and acquired hydrocephalus (RR 2.58, p value < 0.0001) but not for that caused by hydrocephalus with spina bifida (RR 0.65, p value < 0.0001). From 1979 to 1998, the mortality rate due to congenital hydrocephalus declined 66.3%, from spina bifida with hydrocephalus it declined by 30.4%, and from acquired hydrocephalus it declined by 67.5%. Mortality rates from childhood hydrocephalus have declined in US children over the previous 20 years. Black race is associated with higher mortality rates in infants for both congenital and acquired hydrocephalus, whereas sex has no effect.


Aging issues: nursing imperatives for healthcare reform.
The people of the United States sent a clear message in November 2008 that they wanted a change in the nation's priorities, including healthcare. The question is whether healthcare reform will extend to the care of older adults, especially in the face of complex needs in the last years of their lives. This article addresses this question by examining the demographics of the older adult population, the eldercare workforce, and the current inadequate patchwork of financing. Some aging issues, such as chronic care, are being addressed in the broad context of healthcare reform, whereas health information technology and others remain marginal. The window of opportunity for a clear and coherent voice in a reformed/reshaped healthcare system is narrow. Now is the time for the "trusted" profession to advocate for meaningful change that will meet the current and future needs of older adults. The article concludes with strategies and Web-based resources for nurses to bring aging issues to the healthcare reform debate at both the national and local levels.


A Social Media mHealth Solution to Address the Needs of Dengue Prevention and Management in Sri Lanka.
Sri Lanka has witnessed a series of dengue epidemics over the past five years, with the western province, home to the political capital of Colombo, bearing more than half of the dengue burden. Existing dengue monitoring prevention programs are exhausted as public health inspectors (PHIs) cope with increasing workloads and paper-based modes of surveillance and education, characterizing a reactive system unable to cope with the enormity of the problem. On the other hand, the unprecedented proliferation and affordability of mobile phones since 2009 and a supportive political climate have thus far remained unexploited for the use of mobile-based interventions for dengue management. To conduct a needs assessment of PHIs in Colombo with respect to their dengue-related tasks and develop a new mobile-based system to address these needs while strengthening existing systems. One-on-one in-depth interviews were conducted with 29 PHIs to a) gain a nuanced, in-depth understanding of the current state of surveillance practices, b) understand the logistical, technological and social challenges they confront, and c) identify opportunities for mobile-based interventions. Quantitative analysis included simple descriptive statistics while qualitative analysis comprised textual analysis of 209 pages of transcripts (or nearly 600 minutes of conversations) using grounded theory approaches. Current paper-based data collection practices for dengue surveillance involved a circuitous, time consuming process that could take between 7-10 days to officially report and record a single case. PHIs confronted challenges in terms of unreliable, standalone GIS devices, delays in registering mosquito breeding sites and lack of engagement from communities while delivering dengue education. These findings, in concert with a high motivation to use mobile-based systems, informed the development of Mo-Buzz, a mobile-based system that integrates three components - digitized surveillance, dynamic disease mapping and digitized dengue education - on a common platform. The system was developed through an iterative, evolutionary, collaborative process, consistent with the Spiral model of software development and is currently being used by all 55 PHIs in the CMC system. Given the entrenched nature of existing paper-based systems in PHIs' work habits, we expect a gradual adoption curve for Mo-Buzz in the future. Equally, we expect variable adoption of the system with respect to its specific components, and specific PHI sub-groups (younger versus older). The Mo-Buzz intervention is a response to multiple calls by the global mHealth community for collaborations in the area of mobile interventions for global health. Our experience revealed that the benefits of this paradigm lies in alleviating country-specific public health challenges through a commonly shared understanding of cultural mores, and sharing of knowledge and technologies. We call upon future researchers to further dissect the applicability of the Spiral Model of software development to mHealth interventions and contribute to the mHealth evidence debate from theoretical and applied perspectives.


Effect of Plaque Burden and Morphology on Myocardial Blood Flow and Fractional Flow Reserve.
Atherosclerotic plaque characteristics may affect downstream myocardial perfusion, as well as coronary lesion severity. This study sought to evaluate the association between quantitative plaque burden and plaque morphology obtained using coronary computed tomography angiography (CTA) and quantitative myocardial perfusion obtained using [15O]H2O positron emission tomography (PET), as well as fractional flow reserve (FFR) derived invasively. Two hundred eight patients (63% men; age 58 ± 8.7 years) with suspected coronary artery disease were prospectively included. All patients underwent 256-slice coronary CTA, [15O]H2O PET, and invasive FFR measurements. Coronary CTA-derived plaque burden and morphology were assessed using commercially available software and compared with PET perfusion and FFR. Atherosclerotic plaques were present in 179 patients (86%) and 415 of 610 (68%) evaluable coronary arteries. On a per-vessel basis, traditional coronary plaque burden indexes, such as plaque length and volume, minimal lumen area, and stenosis percentage, were significantly associated with impaired hyperemic myocardial blood flow (MBF) and FFR. In addition, morphological features, such as partially calcified plaques, positive remodeling (PR), and low attenuation plaque, displayed a negative impact on hyperemic MBF and FFR. Multivariable analysis revealed that the morphological feature of PR was independently related to impaired hyperemic MBF as well as an unfavorable FFR (p = 0.004 and p = 0.007, respectively), next to stenosis percentage (p = 0.001 and p < 0.001, respectively) and noncalcified plaque volume (p < 0.001 and p = 0.010, respectively). PR and noncalcified plaque volume are associated with detrimental downstream hyperemic myocardial perfusion and FFR, independent of lesion severity.


Potential of helical tomotherapy to reduce dose to the ocular structures for patients treated for unresectable sinonasal cancer.
To compare intensity-modulated radiotherapy (IMRT) treatment plans generated by segmental multileaf collimator (SMLC) and helical tomotherapy (HT) techniques for patients with unresectable sinonasal cancer. SMLC-IMRT and HT-IMRT plans for 5 patients with cancer of the paranasal sinuses and nasal cavity were independently optimized using the Eclipse treatment planning system (Varian Medial Systems, Palo Alto, CA) and Tomotherapy HI-ART treatment planning system (Tomotherapy, Inc, Madison, WI). The goal was to deliver a prescribed dose of 70 Gy to at least 95% of the planning target volume (PTV) encompassing gross tumor over 35 treatments whereas respecting constraints to organs at risk, notably the ocular structures. HT-IMRT reduced the maximum doses to the optic chiasm, as well as to the ipsilateral optic nerve and retina (P < 0.05, for all). Maximum doses to these structures were reduced by 10%, 16%, and 14%, respectively, using HT-IMRT compared with SMLC-IMRT. Additionally, the mean dose to the ipsilateral lacrimal gland was reduced by 32% using HT-IMRT. With respect to conformality, HT-IMRT improved dose homogeneity by decreasing "hot-spots." The mean percentage of PTV70 receiving greater than 77 Gy (110% of the prescribed dose) was 4.0% for the HT-IMRT plans compared with 17.8% for the SMLC-IMRT plans (P = 0.001). HT-IMRT has the potential to improve dose homogeneity to PTVs whereas reducing dose to the optic structures. Clinical implications are discussed.


A cross-sectional study of 'yaws' in districts of Ghana which have previously undertaken azithromycin mass drug administration for trachoma control.
Yaws, caused by Treponema pallidum ssp. pertenue, is reportedly endemic in Ghana. Mass distribution of azithromycin is now the cornerstone of the WHO yaws eradication campaign. Mass distribution of azithromycin at a lower target dose was previously undertaken in two regions of Ghana for the control of trachoma. Ongoing reporting of yaws raises the possibility that resistance may have emerged in T. pallidum pertenue, or that alternative infections may be responsible for some of the reported cases. We conducted a cross-sectional survey in thirty communities in two districts of Ghana where MDA for trachoma had previously been conducted. Children aged 5-17 years with ulcerative lesions compatible with yaws were enrolled. Samples for treponemal serology and lesion PCR were collected from all children. 90 children with 98 lesions were enrolled. Syphilis serology was negative in all of them. PCR for T. pallidum ssp pertenue was negative in all children, but Haemophilus ducreyi DNA was detected in 9 lesions. In these communities, previously treated for trachoma, we found no evidence of ongoing transmission of yaws. H. ducreyi was associated with a proportion of skin lesions, but the majority of lesions remain unexplained. Integration of diagnostic testing into both pre and post-MDA surveillance systems is required to better inform yaws control programmes.


Electrophoretic deposition: a versatile tool against biomaterial associated infections.
Biomaterial-associated infections (BAIs) are today considered as one of the most withering complications of orthopedic implant surgery. Even though BAIs occur relatively infrequently in primary joint replacement surgeries (incidence rates around 1-2%), revision arthroplasties carry up to 40% risk of infection recurrence, with devastating consequences for the patient and significant associated cost. Once the responsible pathogens, mainly bacteria, attach to the surface of the biomaterial, they start creating layers of extracellular matrix with complex architectures, called biofilms. These last mentioned, encapsulate and protect bacteria by hindering the immune response and impeding antibiotics from reaching the pathogens. To prevent such an outcome, the surface of the biomaterials, in particular implants, can be modified in order to play the role of inherent drug delivery devices or as substrates for antibacterial/multifunctional coating deposition. This paper presents an overview of novel electrochemically-triggered deposition strategies, with a focus on electrophoretic deposition (EPD), a versatile and cost-effective technique for organic and inorganic material deposition. Other than being a simple deposition tool, EPD has been recently employed to create novel micro/nanostructured surfaces for multi-purpose antibacterial approaches, presented in detail in this review. In addition, a thorough comparison and assessment of the latest antibacterial and multifunctional compounds deposited by means of EPD have been reported, followed by a critical reflection on current and future prospects of the topic. The relative simplicity of EPD's application, has, by some means, undermined the fundamental requirement of rationality of multifunctional coating design. The demanding practical needs for a successful clinical translation in the growing fields of tissue engineering and antibacterial/multifunctional implant coatings, calls for a more systematic in vitro experimental design rationale, in order to make amends for the scarcity of significant in vivo and clinical studies.


Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.
Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis and in vivo multispectral noninvasive imaging during the S. aureus infection revealed a strong functional and temporal association between neutrophil recruitment and IL-1β/IL-1R activation. Unexpectedly, neutrophils but not monocytes/macrophages or other MHCII-expressing antigen presenting cells were the predominant source of IL-1β at the site of infection. Furthermore, neutrophil-derived IL-1β was essential for host defense since adoptive transfer of IL-1β-expressing neutrophils was sufficient to restore the impaired neutrophil abscess formation in S. aureus-infected IL-1β-deficient mice. S. aureus-induced IL-1β production by neutrophils required TLR2, NOD2, FPR1 and the ASC/NLRP3 inflammasome in an α-toxin-dependent mechanism. Taken together, IL-1β and neutrophil abscess formation during an infection are functionally, temporally and spatially linked as a consequence of direct IL-1β production by neutrophils.


Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report.
Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.