Model of human visual-motion sensing.
We propose a model of how humans sense the velocity of moving images. The model exploits constraints provided by human psychophysics, notably that motion-sensing elements appear tuned for two-dimensional spatial frequency, and by the frequency spectrum of a moving image, namely, that its support lies in the plane in which the temporal frequency equals the dot product of the spatial frequency and the image velocity. The first stage of the model is a set of spatial-frequency-tuned, direction-selective linear sensors. The temporal frequency of the response of each sensor is shown to encode the component of the image velocity in the sensor direction. At the second stage, these components are resolved in order to measure the velocity of image motion at each of a number of spatial locations and spatial frequencies. The model has been applied to several illustrative examples, including apparent motion, coherent gratings, and natural image sequences. The model agrees qualitatively with human perception.


[Bispecific antibodies, novel therapeutic candidates harnessing the immune system].
Over the past ten years, an increased knowledge of tumor biology and immunology allowed the design and development of novel therapeutic antibody and protein scaffold formats, where bispecific antibodies (Abs) play a major role. The latter molecules can (1) bring novel pharmacological properties through the co-engagement of two targets, (2) increase the safety profile as compared to a combination of two antibodies thanks to a targeted relocation to the tumor and (3) reduce development and manufacturing costs associated with single drug product. This review analyzes the different bispecific antibodies and scaffolds described in the field of immuno-oncology, their structure and major pharmacological and physico-chemical properties.


Patient-perceived differences between constant current and constant voltage spinal cord stimulation systems.
Spinal cord stimulation (SCS) systems employ implantable pulse generators that use either a constant current (CC) or a constant voltage (CV) power source. CC power sources adjust voltage in response to resistance (impedance) to ensure that consistent current is delivered to the patient. CV power sources do not adjust voltage in response to impedance; therefore, current delivered to the patient will vary in response to changes in impedance. Both systems produce paresthesia and have been shown to treat chronic pain; however, it has been suggested that patients prefer CC stimulation over CV stimulation. This Institutional Review Board-approved, randomized, double-blinded crossover study compared patient preference for the stimulation sensation elicited by a CC or CV neurostimulation system. Thirty patients completed a baseline evaluation prior to implantation of a percutaneous trial system and returned one-day postimplant for randomization and initiation of SCS. Three days later, patients were evaluated and crossed over into the alternate treatment group. Final evaluation of patient well-being, pain relief, satisfaction, quality of life, preference, and stimulation sensation occurred on Day 6. Patient preference was assessed using a one-sample Z-test. Treatment and group differences were explored using paired t-test for continuous and ordinal variables and chi-square of Fisher's exact test for categorical variables. More patients (70%) preferred CC stimulation over CV stimulation (30%), and CC stimulation produced a significantly larger decrease in pain scores than CV stimulation. Interestingly, patients initially exposed to CC stimulation were less likely to be satisfied with CV stimulation. The results from this study indicate that patients preferred and experienced greater satisfaction and pain relief with the CC system during an SCS trial period. Differences between the two systems following long-term use has yet to be compared. However, the benefits of the CC system seen with short-term use should be considered when selecting an SCS system.


Kinematic, kinetic and EMG patterns during downward squatting.
The aim of this study was to investigate the kinematic, kinetic, and electromyographic pattern before, during and after downward squatting when the trunk movement is restricted in the sagittal plane. Eight healthy subjects performed downward squatting at two different positions, semisquatting (40 degrees knee flexion) and half squatting (70 degrees knee flexion). Electromyographic responses of the vastus medialis oblique, vastus medialis longus, rectus femoris, vastus lateralis, biceps femoris, semitendineous, gastrocnemius lateralis, and tibialis anterior were recorded. The kinematics of the major joints were reconstructed using an optoelectronic system. The center of pressure (COP) was obtained using data collected from one force plate, and the ankle and knee joint torques were calculated using inverse dynamics. In the upright position there were small changes in the COP and in the knee and ankle joint torques. The tibialis anterior provoked the disruption of this upright position initiating the squat. During the acceleration phase of the squat the COP moved posteriorly, the knee joint torque remained in flexion and there was no measurable muscle activation. As the body went into the deceleration phase, the knee joint torque increased towards extension with major muscle activities being observed in the four heads of the quadriceps. Understanding these kinematic, kinetic and EMG strategies before, during and after the squat is expected to be beneficial to practitioners for utilizing squatting as a task for improving motor function.


Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis.
Purpose: Pancreatic cancer is one of the most lethal of solid tumors and is associated with aggressive cancer biology. The purpose is to review the role of trypsin and effect on molecular and cellular processes potentially explaining the aggressive biology in pancreatic cancer. Methods: A narrative literature review of studies investigating trypsin and its effect on protease systems in cancer, with special reference to pancreatic cancer biology. Results: Proteases, such as trypsin, provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Trypsin is a digestive enzyme produced by the exocrine pancreas that is also related to mechanisms of proliferation, invasion and metastasis. Several of these mechanisms may be co-regulated or influenced by activation of proteinase-activated receptor 2 (PAR-2). The current role in pancreatic cancer is not clear but emerging data suggest several potential mechanisms. Trypsin may act as a Trojan horse in the pancreatic gland, facilitating several molecular pathways from the onset, which leads to rapid progression of the disease. Pancreatic cancer cell lines containing PAR-2 proliferate upon exposure to trypsin, whereas cancer cell lines not containing PAR-2 fail to proliferate upon trypsin expression. Several mechanisms of action include a proinflammatory environment, signals inducing proliferation and migration, and direct and indirect evidence for mechanisms promoting invasion and metastasis. Novel techniques (such as organoid models) and increased understanding of mechanisms (such as the microbiome) may yield improved understanding into the role of trypsin in pancreatic carcinogenesis. Conclusion: Trypsin is naturally present in the pancreatic gland and may experience pathological activation intracellularly and in the neoplastic environment, which speeds up molecular mechanisms of proliferation, invasion, and metastasis. Further investigation of these processes will provide important insights into how pancreatic cancer evolves, and suggest new ways for treatment.


Optimal inversion of the Anscombe transformation in low-count Poisson image denoising.
The removal of Poisson noise is often performed through the following three-step procedure. First, the noise variance is stabilized by applying the Anscombe root transformation to the data, producing a signal in which the noise can be treated as additive Gaussian with unitary variance. Second, the noise is removed using a conventional denoising algorithm for additive white Gaussian noise. Third, an inverse transformation is applied to the denoised signal, obtaining the estimate of the signal of interest. The choice of the proper inverse transformation is crucial in order to minimize the bias error which arises when the nonlinear forward transformation is applied. We introduce optimal inverses for the Anscombe transformation, in particular the exact unbiased inverse, a maximum likelihood (ML) inverse, and a more sophisticated minimum mean square error (MMSE) inverse. We then present an experimental analysis using a few state-of-the-art denoising algorithms and show that the estimation can be consistently improved by applying the exact unbiased inverse, particularly at the low-count regime. This results in a very efficient filtering solution that is competitive with some of the best existing methods for Poisson image denoising.


Global DNA methylation: a common early event in oral cancer cases with exposure to environmental carcinogens or viral agents.
Two separate molecular pathways have been proposed for the early carcinogenic events observed in the oral cavity and pharynx: one is associated with chemical etiological factors such as smoking and drinking, and the other one is associated with HPV insertion. A proof-of-principle study was performed to ascertain if global DNA methylation could be used to distinguish between the early molecular changes in premalignant oral lesions. Personal histories of tobacco and alcohol use were obtained by questionnaire. HPV insertion in tumor tissue was detected by polymerase chain reaction (PCR). Global DNA methylation levels were obtained using HPLC for fraction separation and mass spectrometry for quantification. Predictive simulations were performed to explore potential associations between different etiological factors and the global DNA methylation index. Significance of results was ascertained using Pearson's Chi-squared test. The global methylation index was found to be 4.28 (95% CI, 4.1, 4.4) in an oral cancer case series. Pearson's chi squared test showed no statistically significant difference between cases that had smoking (p = 0.21), drinking (p = 0.31) or HPV insertion (p = 0.34) as etiologic risk factors, when compared to cases that did not. An inverse significant association between smoking and DNA methylation was observed. As the smoking effect increases, the global methylation index decreases, In addition, no associations between the probability of DNA methylation and drinking, or DNA methylation and HPV insertion were observed in simulations. The global DNA methylation index was shown to vary for oral cancer cases with different etiologies. Smoking was inversely correlated with DNA methylation levels when generalized linear model simulations were performed. Future studies should look at global DNA methylation alterations associated to the progression from normal to premalignant oral epithelium tissue in a cohort of smokers and nonsmokers.


Profiling Shoulder Strength in Competitive Surfers.
The shoulder region has the highest incidence of acute injuries in the sport of surfing. Little is known about the strength profile at the shoulder in a surfing cohort. The primary aim of this study was to establish the reliability of a rotator cuff strength testing procedure for surfers with a secondary aim of providing a profile of internal and external rotation strength in a competitive surfing cohort. Shoulder internal rotation and external rotation isometric strength was measured using a hand-held dynamometer in 13 competitive surfers. Intra-class coefficient values ranged from 0.97 to 0.98 for intra-rater reliability and were lower for inter-rater reliability ranging from 0.80 to 0.91. Internal rotation strength was greater than external rotation strength bilaterally (dominant, p = 0.007, non-dominant, p < 0.001). No differences (p < 0.79) were found in internal rotation strength between the dominant and non-dominant arms. External rotation strength was weaker on the non-dominant arm compared with the dominant arm (p < 0.02). The non-dominant arm external rotation to internal rotation ratio (0.82 ± 0.15) was lower (p = 0.025) than the dominant arm (0.88 ± 0.14). The current procedure is reliable with the same clinician, and results indicate musculature asymmetry specific to the external rotators.


The inhalation of drugs: advantages and problems.
Inhalation is a very old method of drug delivery, and in the 20th century it became a mainstay of respiratory care, known as aerosol therapy. Use of inhaled epinephrine for relief of asthma was reported as early as 1929, in England. An early version of a dry powder inhaler (DPI) was the Aerohalor, used to administer penicillin dust to treat respiratory infections. In the 1950s, the Wright nebulizer was the precursor of the modern hand-held jet-venturi nebulizer. In 1956, the first metered-dose inhaler (MDI) was approved for clinical use, followed by the SpinHaler DPI for cromolyn sodium in 1971. The scientific basis for aerosol therapy developed relatively late, following the 1974 Sugarloaf Conference on the scientific basis of respiratory therapy. Early data on the drug-delivery efficiency of the common aerosol delivery devices (MDI, DPI, and nebulizer) showed lung deposition of approximately 10-15% of the total, nominal dose. Despite problems with low lung deposition with all of the early devices, evidence accumulated that supported the advantages of the inhalation route over other drug-administration routes. Inhaled drugs are localized to the target organ, which generally allows for a lower dose than is necessary with systemic delivery (oral or injection), and thus fewer and less severe adverse effects. The 3 types of aerosol device (MDI, DPI, and nebulizer) can be clinically equivalent. It may be necessary to increase the number of MDI puffs to achieve results equivalent to the larger nominal dose from a nebulizer. Design and lung-deposition improvement of MDIs, DPIs, and nebulizers are exemplified by the new hydrofluoroalkane-propelled MDI formulation of beclomethasone, the metered-dose liquid-spray Respimat, and the DPI system of the Spiros. Differences among aerosol delivery devices create challenges to patient use and caregiver instruction. Potential improvements in aerosol delivery include better standardization of function and patient use, greater reliability, and reduction of drug loss.


[The transfer of critically ill patients].
Critically ill patients admitted to an intensive care unit or an emergency ward, frequently need to be transported to different areas within the hospital in order to perform diagnostic procedures. An increased mortality and morbidity risk has been found associated with the transportation of these patients. In order to investigate the effect of the intra-hospitalary transport of our patients on their clinical status this study was conducted. We studied 12 patients admitted to the intensive care unit or the emergency ward; all were on mechanical-assisted ventilation and had been stable for at least six hours prior to transportation. Blood gas and hemodynamic measurements were obtained before, immediately after and thirty minutes after transportation. The most significant changes seen immediately in our patients were an increase in PaCO2 (30.8 +/- 7.35 vs 35.6 +/- 7.49, p less than 0.02) and a decrease in pH (7.36 +/- 0.08 vs 7.31 +/- 0.05, p less than 0.02). Patients with higher pH values prior to their transportation had the most significant change towards acidosis (r = -0.79). All changes reversed thirty minutes after reinstallation of the mechanical ventilation. There was no change in the hemodynamic measurements. We conclude that the transportation of critically ill patients within a hospital is fairly safe if patients are previously stabilized.


Tackling antibiotic resistance: the environmental framework.
Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment.


Rapid Mobilization of Noncrystalline U(IV) Coupled with FeS Oxidation.
The reactivity of disordered, noncrystalline U(IV) species remains poorly characterized despite their prevalence in biostimulated sediments. Because of the lack of crystalline structure, noncrystalline U(IV) may be susceptible to oxidative mobilization under oxic conditions. The present study investigated the mechanism and rate of oxidation of biogenic noncrystalline U(IV) by dissolved oxygen (DO) in the presence of mackinawite (FeS). Previously recognized as an effective reductant and oxygen scavenger, nanoparticulate FeS was evaluated for its role in influencing U release in a flow-through system as a function of pH and carbonate concentration. The results demonstrated that noncrystalline U(IV) was more susceptible to oxidation than uraninite (UO2) in the presence of dissolved carbonate. A rapid release of U occurred immediately after FeS addition without exhibiting a temporary inhibition stage, as was observed during the oxidation of UO2, although FeS still kept DO levels low. X-ray photoelectron spectroscopy (XPS) characterized a transient surface Fe(III) species during the initial FeS oxidation, which was likely responsible for oxidizing noncrystalline U(IV) in addition to oxygen. In the absence of carbonate, however, the release of dissolved U was significantly hindered as a result of U adsorption by FeS oxidation products. This study illustrates the strong interactions between iron sulfide and U(IV) species during redox transformation and implies the lability of biogenic noncrystalline U(IV) species in the subsurface environment when subjected to redox cycling events.


Prenatal famine exposure, health in later life and promoter methylation of four candidate genes.
Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944-45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.


Pregnancies complicated by both preeclampsia and growth restriction between 34 and 37 weeks' gestation are associated with adverse perinatal outcomes.
To determine whether adverse outcomes were more common in late preterm pregnancies complicated by preeclampsia and growth restriction compared to those affected by preeclampsia alone. This was a retrospective cohort study of 8927 singleton pregnancies with preeclampsia. Pregnancies with small for gestational age (SGA) neonates (birth weight <10th percentile) were compared to those appropriate for gestational age (AGA) neonates. Maternal outcomes included cesarean delivery (CD) rate, CD for fetal heart rate (FHR) abnormalities, abruption, postpartum hemorrhage (PPH), maternal transfusion, acute renal failure, and peripartum cardiomyopathy. Neonatal outcomes studied included respiratory distress syndrome (RDS), jaundice, hypoglycemia, seizure, asphyxia, neonatal death, and intrauterine fetal demise (IUFD). Women with preeclampsia and SGA infants were more likely to experience abruption (5.3% versus 3.0%, p < 0.001), higher CD rate (66.5% versus 55.0%, p < 0.001), and higher likelihood of a CD for FHR abnormalities (21.7% versus 10.0%, p < 0.001). SGA infants were more likely to experience adverse neonatal outcomes including RDS (10.1% versus 4.9%, p < 0.001), jaundice (59.8% versus 39.2%, p < 0.001), hypoglycemia (8.9% versus 3.9%, p < 0.001), asphyxia (0.6% versus 0.2%, p = 0.015), and IUFD (1.5% versus 0.3%, p < 0.001). Preeclamptic women and their neonates were more likely to experience adverse perinatal outcomes when SGA pregnancies were compared to those with AGA neonates.


Multiple levels of letter representation in written spelling: evidence from a single case of dysgraphia with multiple deficits.
In this paper, we report a detailed analysis of the impaired performance of a dysgraphic individual, AD, who produced similar rates of letter-level errors in written spelling, oral spelling, and typing. We found that the distribution of various letter error types displayed a distinct pattern in written spelling on the one hand and in oral spelling and typing on the other. In particular, noncontextual letter substitution errors (i.e., errors in which the erroneous letter that replaces the target letter does not occur elsewhere within the word) were virtually absent in oral spelling and typing and mainly found in written spelling. In contrast, letter deletion errors and multiple-letter errors were typically found in oral spelling and very exceptional in written spelling. Only contextual letter substitution errors (i.e., errors in which the erroneous letter that replaces the target letter is identical to a letter occurring earlier or later in the word) were found in similar proportions in the three tasks. We argue that these contrasting patterns of letter error distribution result from damage to two distinct levels of letter representation and processing within the spelling system, namely, the amodal graphemic representation held in the graphemic buffer and the letter form representation computed by subsequent writing-specific processes. Then, we examined the relationship between error and target in the letter substitution errors produced in written and oral spelling and found evidence that distinct types of letter representation are processed at each of the hypothetized levels of damage: symbolic letter representation at the graphemic level and representation of the component graphic strokes at the letter form processing level.


Asymmetric Mbc, active Rac1 and F-actin foci in the fusion-competent myoblasts during myoblast fusion in Drosophila.
Myoblast fusion is an intricate process that is initiated by cell recognition and adhesion, and culminates in cell membrane breakdown and formation of multinucleate syncytia. In the Drosophila embryo, this process occurs asymmetrically between founder cells that pattern the musculature and fusion-competent myoblasts (FCMs) that account for the bulk of the myoblasts. The present studies clarify and amplify current models of myoblast fusion in several important ways. We demonstrate that the non-conventional guanine nucleotide exchange factor (GEF) Mbc plays a fundamental role in the FCMs, where it functions to activate Rac1, but is not required in the founder cells for fusion. Mbc, active Rac1 and F-actin foci are highly enriched in the FCMs, where they localize to the Sns:Kirre junction. Furthermore, Mbc is crucial for the integrity of the F-actin foci and the FCM cytoskeleton, presumably via its activation of Rac1 in these cells. Finally, the local asymmetric distribution of these proteins at adhesion sites is reminiscent of invasive podosomes and, consistent with this model, they are enriched at sites of membrane deformation, where the FCM protrudes into the founder cell/myotube. These data are consistent with models promoting actin polymerization as the driving force for myoblast fusion.


Renal transplantation between male and female spontaneously hypertensive rats.
The higher blood pressures of male compared with female spontaneously hypertensive rats (SHR) are the result of the inheritance of different sex chromosomes, although the pathophysiology has not been defined clearly. The reported hypertensive effect of kidneys transplanted from male SHR raises the possibility of a sex-specific renal abnormality, but the effects of transplanting female SHR kidneys have not been studied. To test this hypothesis, single kidneys were transplanted from male SHR into female SHR recipients and vice versa, followed by removal of the native kidneys of the recipients. Male and female SHR that had undergone uninephrectomy were used as controls. After surgery at 14 weeks of age, systolic blood pressures were measured each week until 30 weeks of age. The replacement of a SHR female kidney with a SHR male kidney was not associated with any significant rise in blood pressure, and the replacement of a SHR male kidney with a kidney from a female SHR was not associated with any reduction in blood pressure. These results indicate that the sexual dimorphism of SHR blood pressure is not the result of intrinsic renal differences between males and females and that nonrenal factors would be more likely to explain the blood pressure differences between the sexes.


Differences in forest plant functional trait distributions across land-use and productivity gradients.
Plant functional traits are commonly used as proxies for plant responses to environmental challenges, yet few studies have explored how functional trait distributions differ across gradients of land-use change. By comparing trait distributions in intact forests with those across land-use change gradients, we can improve our understanding of the ways land-use change alters the diversity and functioning of plant communities. We examined how the variation and distribution of trait values for seven plant functional traits differ between reference natural forest and three types of land-use conversion (pasture, old-field, or "legacy" sites-regrowth following logging), landscape productivity (NPP) and vegetation strata (tree or non-tree "understory"), in a meta-analysis of studies from 15 landscapes across five continents. Although trait variation often differed between land-uses within a landscape, these patterns were rarely consistent across landscapes. The variance and distribution of traits were more likely to differ consistently between natural forest and land-use conversion categories for understory (non-tree) plants than for trees. Landscape productivity did not significantly alter the difference in trait variance between natural forest and land-use conversion categories for any trait except dispersal. Our results suggest that even for traits well linked to plant environmental response strategies, broad classes of land-use change and landscape productivity are not generally useful indicators of the mechanisms driving compositional changes in human-modified forest systems.


Antibacterial Activity and Multi-Targeting Mechanism of Dehydrocorydaline From Corydalis turtschaninovii Bess. Against Listeria monocytogenes.
Listeria monocytogenes is a foodborne pathogen, with relatively low incidence but high case-fatality. Phytochemicals have been recognized as a promising antimicrobial agent as an alternative to synthetic chemicals due to their safety and high efficacy with multi-target sites. This study identified and characterized a novel antibacterial agent, dehydrocorydaline, in the Corydalis turschaninovii rhizome using HPLC-LTQ-Orbitrap-HRMS, and its antibacterial effect with lowest MIC (1 mg/mL) and MBC (2 mg/mL) values. In addition, an in vitro growth kinetic assay, cytoplasmic nucleic acid and protein leakage assay, and observation of morphological changes in bacterial cells supported the strong antibacterial activity. Dehydrocorydaline also displayed effective inhibitory effects on biofilm formation and bacterial motility. In order to investigate the potential antibacterial mechanism of action of dehydrocorydaline against L. monocytogenes, label-free quantitative proteomics was used, demonstrating that dehydrocorydaline has multiple targets for combating L. monocytogenes including dysregulation of carbohydrate metabolism, suppression of cell wall synthesis, and inhibition of bacterial motility. Overall, this study demonstrated that dehydrocorydaline has potential as a natural and effective antibacterial agent with multi-target sites in pathogenic bacteria, and provides the basis for development of a new class of antibacterial agent.


Neuro, trauma, or med/surg intensive care unit: Does it matter where multiple injuries patients with traumatic brain injury are admitted? Secondary analysis of the American Association for the Surgery of Trauma Multi-Institutional Trials Committee decompressive craniectomy study.
Patients with nontraumatic acute intracranial pathology benefit from neurointensivist care. Similarly, trauma patients with and without traumatic brain injury (TBI) fare better when treated by a dedicated trauma team. No study has yet evaluated the role of specialized neurocritical (NICU) and trauma intensive care units (TICU) in the management of TBI patients, and it remains unclear which TBI patients are best served in NICU, TICU, or general (Med/Surg) ICU. This study is a secondary analysis of The American Association for the Surgery of Trauma Multi-Institutional Trials Committee (AAST-MITC) decompressive craniectomy study. Twelve Level 1 trauma centers provided clinical data and head computed tomography (CT) scans of patients with Glasgow Coma Scale score of 13 or less and CT evidence of TBI. Non-ICU admissions were excluded. Multivariate logistic regression was performed to measure the association between ICU type and survival and calculate the probability of death for increasing Injury Severity Score (ISS). Multiple injuries patients (ISS > 15) with TBI and isolated TBI patients (other Abbreviated Injury Scale score < 3) were analyzed separately. There were 3641 patients with CT evidence of TBI with 2951 admitted to an ICU. Before adjustment, patient demographics, injury severity, and survival differed significantly by unit type. After adjustment, unit type, age, and ISS remained independent predictors of death. Unit type modified the effect of ISS on mortality. TBI multiple injuries patients admitted to a TICU had improved survival across increasing ISS. Survival for isolated TBI patients was similar between TICU and NICU. Med/surg ICU carried the greatest probability of death. Multiple injuries patients with TBI have lower mortality risk when admitted to a trauma ICU. This survival benefit increases with increasing injury severity. Isolated TBI patients have similar mortality risk when admitted to a neuro ICU compared with a trauma ICU. Med/surg ICU admission carries the highest mortality risk. Therapeutic study, level IV.


Presynaptic filament dynamics in homologous recombination and DNA repair.
Homologous recombination (HR) is an essential genome stability mechanism used for high-fidelity repair of DNA double-strand breaks and for the recovery of stalled or collapsed DNA replication forks. The crucial homology search and DNA strand exchange steps of HR are catalyzed by presynaptic filaments-helical filaments of a recombinase enzyme bound to single-stranded DNA (ssDNA). Presynaptic filaments are fundamentally dynamic structures, the assembly, catalytic turnover, and disassembly of which must be closely coordinated with other elements of the DNA recombination, repair, and replication machinery in order for genome maintenance functions to be effective. Here, we reviewed the major dynamic elements controlling the assembly, activity, and disassembly of presynaptic filaments; some intrinsic such as recombinase ATP-binding and hydrolytic activities, others extrinsic such as ssDNA-binding proteins, mediator proteins, and DNA motor proteins. We examined dynamic behavior on multiple levels, including atomic- and filament-level structural changes associated with ATP binding and hydrolysis as evidenced in crystal structures, as well as subunit binding and dissociation events driven by intrinsic and extrinsic factors. We examined the biochemical properties of recombination proteins from four model systems (T4 phage, Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens), demonstrating how their properties are tailored for the context-specific requirements in these diverse species. We proposed that the presynaptic filament has evolved to rely on multiple external factors for increased multilevel regulation of HR processes in genomes with greater structural and sequence complexity.


Ophthalmic artery occlusion after Pipeline Embolization Device placement with reconstitution of flow via an endoleak: a report of two cases.
The Pipeline Embolization Device (PED) is a flow diverting stent used in the treatment of a wide variety of intracranial aneurysms. The device differs from traditional stents used in stent-assisted coil embolization in that it has a tighter lattice structure with smaller cell sizes designed specifically to disrupt blood flow into aneurysms rather than only to retain coils within aneurysms. While the PED has been shown to be safe and effective, it has a unique risk profile that includes side branch and perforator vessel occlusion. Side branch occlusion in particular has been noted in several articles to occur at a relatively high rate with coverage of the ophthalmic artery origin by the PED. In this series, we present two cases of ophthalmic artery occlusion after PED placement with reconstitution of flow via an endoleak.


Barriers in accessing maternal healthcare: evidence from low-and middle-income countries.
The goal of improving the health status of people living in developing countries has received increasing priority in recent years. To achieve this goal, evidence is needed regarding methods for optimal allocation of expenditure within particular program areas. Among several competing programs, a commitment has been made to improve maternal health as part of the Millennium Development Goal targets. While there is a growing body of cost-effectiveness evidence relating to maternal healthcare programs, underutilization of services is still pervasive, especially among poorer groups of the population. A major reason for such underutilization lies in underlying adverse socioeconomic factors, or barriers, which impede healthcare use. This article reviews the evidence from studies that have conducted multivariate analyses to quantify the effects of education, economic status and distance barriers on service use. It is concluded that it is not possible to state categorically whether one particular barrier is more important than others and that efforts should continue to consider demand-side barriers more fully, along with supply-side barriers.


Fluorescent-oligonucleotide probing of whole cells for determinative, phylogenetic, and environmental studies in microbiology.
Fluorescent-dye-conjugated oligonucleotides were used to classify 14 Fibrobacter strains by fluorescence microscopy. On the basis of partial 16S rRNA sequences of six Fibrobacter strains, four hybridization probes were designed to discriminate between the species Fibrobacter succinogenes and Fibrobacter intestinalis and to identify F. succinogenes subsp. succinogenes. After in situ hybridization to whole cells of the six sequenced strains, epifluorescence microscopy confirmed probe specificity. The four probes were then used to make presumptive species and subspecies assignments of eight additional Fibrobacter strains not previously characterized by comparative sequencing. These assignments were confirmed by comparative sequencing of the 16S rRNA target regions from the additional organisms. Single-mismatch discrimination between certain probe and nontarget sequences was demonstrated, and fluorescent intensity was shown to be enhanced by hybridization to multiple probes of the same specificity. The direct detection of F. intestinalis in mouse cecum samples demonstrated the application of this technique to the characterization of complex natural samples.


Health beliefs as a key determinant of intent to use anabolic-androgenic steroids (AAS) among high-school football players: implications for prevention.
The use of anabolic-androgenic steroids (AAS) is problematic for youth because of negative effects such as reduced fertility, increased aggression and exposure to toxic chemicals. An effective programme for addressing this problem is Adolescents Training and Learning to Avoid Steroids (ATLAS). This secondary analysis expands prior research by identifying prominent mechanisms of change and highlighting key longitudinal processes that contributed to the success of ATLAS. The current sample consists of high-school football players (N = 1.068; M age = 15.25) who began ATLAS in grades nine through eleven and participated in booster sessions for two years post-baseline. Knowledge of AAS effects, belief in media ads, reasons not to use AAS, perceived severity of and susceptibility to AAS effects and ability to resist drug offers were critical mediators of the relations between ATLAS and outcomes. Modern applications of the ATLAS programme are also discussed.


Bioaccumulation of metals by Fucus ceranoides in estuaries of South West England.
Fucus ceranoides tolerates abiotic conditions encountered across the full range of estuarine salinities. We examined the bioaccumulation of metals in individuals and metal concentrations in accompanying sediment samples collected at different locations along estuaries of South West England. Intra- and inter-estuarine variations in metal accumulation by F. ceranoides, after correction for particulate contamination using Fe as a proxy, were attributed to variations in the availabilities and concentrations of aqueous metals. Greatest accumulation was observed in estuaries that remain most heavily impacted by historical mining activities and for metals that were mobilised to the greatest extent during these operations (As, Cu, Sn, Zn). Arsenic concentrations displayed a seaward increase in estuaries in which multiple samples were taken, whereas Cd concentrations were always greatest in samples collected from the most landward locations. Ongoing research aims to better understand the mechanisms and kinetics of metal interactions with F. ceranoides and their dependence on salinity.


Snakes: hatching of a model system for Evo-Devo?
Evo-Devo studies rely on a collection of animal model systems belonging to different phylogenetic branches to try and understand how organisms carrying a similar set of genes and pathways can develop into such a variety of shapes and sizes. The squamate clade, however, has only recently started to receive the attention it deserves in particular due to extreme morphological and metabolic aspects and, consequently, the important insights that it could bring in different fields. The recent sequencing of several squamate genomes as well as the generation of high quality trancriptomes for different snake tissues now provide the necessary tools to complement biological studies. Here, we briefly report on recent work involving developing snake embryos to illustrate their interest to assess vertebrate developmental mechanisms. We also discuss the relevance to use snake species as Evo-Devo model systems and potential ways to cross the important limitations intrinsically associated with developmental and genetic studies of these fascinating animals.


Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally.
Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied. To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations. In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels. We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient. Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.


Large colonial organisms with coordinated growth in oxygenated environments 2.1 Gyr ago.
The evidence for macroscopic life during the Palaeoproterozoic era (2.5-1.6 Gyr ago) is controversial. Except for the nearly 2-Gyr-old coil-shaped fossil Grypania spiralis, which may have been eukaryotic, evidence for morphological and taxonomic biodiversification of macroorganisms only occurs towards the beginning of the Mesoproterozoic era (1.6-1.0 Gyr). Here we report the discovery of centimetre-sized structures from the 2.1-Gyr-old black shales of the Palaeoproterozoic Francevillian B Formation in Gabon, which we interpret as highly organized and spatially discrete populations of colonial organisms. The structures are up to 12 cm in size and have characteristic shapes, with a simple but distinct ground pattern of flexible sheets and, usually, a permeating radial fabric. Geochemical analyses suggest that the sediments were deposited under an oxygenated water column. Carbon and sulphur isotopic data indicate that the structures were distinct biogenic objects, fossilized by pyritization early in the formation of the rock. The growth patterns deduced from the fossil morphologies suggest that the organisms showed cell-to-cell signalling and coordinated responses, as is commonly associated with multicellular organization. The Gabon fossils, occurring after the 2.45-2.32-Gyr increase in atmospheric oxygen concentration, may be seen as ancient representatives of multicellular life, which expanded so rapidly 1.5 Gyr later, in the Cambrian explosion.


Synthesis of unsaturated phosphatidylinositol 4-phosphates and the effects of substrate unsaturation on SopB phosphatase activity.
In this paper evidence is presented that the fatty acid component of an inositide substrate affects the kinetic parameters of the lipid phosphatase Salmonella Outer Protein B (SopB). A succinct route was used to prepare the naturally occurring enantiomer of phosphatidylinositol 4-phosphate (PI-4-P) with saturated, as well as singly, triply and quadruply unsaturated, fatty acid esters, in four stages: (1) The enantiomers of 2,3:5,6-O-dicyclohexylidene-myo-inositol were resolved by crystallisation of their di(acetylmandelate) diastereoisomers. (2) The resulting diol was phosphorylated regio-selectively exclusively on the 1-O using the new reagent tri(2-cyanoethyl)phosphite. (3) With the 4-OH still unprotected, the glyceride was coupled using phosphate tri-ester methodology. (4) A final phosphorylation of the 4-O, followed by global deprotection under basic then acidic conditions, provided PI-4-P bearing a range of sn-1-stearoyl, sn-2-stearoyl, -oleoyl, -γ-linolenoyl and arachidonoyl, glycerides. Enzymological studies showed that the introduction of cis-unsaturated bonds has a measurable influence on the activity (relative Vmax) of SopB. Mono-unsaturated PI-4-P exhibited a five-fold higher activity, with a two-fold higher KM, over the saturated substrate, when presented in DOPC vesicles. Poly-unsaturated PI-4-P showed little further change with respect to the singly unsaturated species. This result, coupled with our previous report that saturated PI-4-P has much higher stored curvature elastic stress than PI, supports the hypothesis that the activity of inositide phosphatase SopB has a physical role in vivo.


Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst.
Chemists extensively use free radical reactivity for applications in organic synthesis, materials science, and life science. Traditionally, generating radicals requires strategies that exploit the bond dissociation energy or the redox properties of the precursors. Here, we disclose a photochemical catalytic approach that harnesses different physical properties of the substrate to form carbon radicals. We use a nucleophilic dithiocarbamate anion catalyst, adorned with a well-tailored chromophoric unit, to activate alkyl electrophiles via an SN2 pathway. The resulting photon-absorbing intermediate affords radicals upon homolytic cleavage induced by visible light. This catalytic SN2-based strategy, which exploits a fundamental mechanistic process of ionic chemistry, grants access to open-shell intermediates from a variety of substrates that would be incompatible with or inert to classical radical-generating strategies. We also describe how the method's mild reaction conditions and high functional group tolerance could be advantageous for developing C-C bond-forming reactions, for streamlining the preparation of a marketed drug, for the late-stage elaboration of biorelevant compounds and for enantioselective radical catalysis.


Integrated multi-omics analysis reveals the underlying molecular mechanism for developmental neurotoxicity of perfluorooctanesulfonic acid in zebrafish.
Limited studies on multi-omics have been conducted to comprehensively investigate the molecular mechanism underlying the developmental neurotoxicity of perfluorooctanesulfonic acid (PFOS). In this study, the locomotor behavior of zebrafish larvae was assessed under the exposure to 0.1-20 μM PFOS based on its reported neurobehavioral effect. After the number of zebrafish larvae was optimized for proteomics and metabolomics studies, three kinds of omics (i.e., transcriptomics, proteomics, and metabolomics) were carried out with zebrafish larvae exposed to 0.1, 1, 5, and 10 μM PFOS. More importantly, a data-driven integration of multi-omics was performed to elucidate the toxicity mechanism involved in developmental neurotoxicity. In a concentration-dependent manner, exposure to PFOS provoked hyperactivity and hypoactivity under light and dark conditions, respectively. Individual omics revealed that PFOS exposure caused perturbations in the pathways of neurological function, oxidative stress, and energy metabolism. Integrated omics implied that there were decisive pathways for axonal deformation, neuroinflammatory stimulation, and dysregulation of calcium ion signaling, which are more clearly specified for neurotoxicity. Overall, our findings broaden the molecular understanding of the developmental neurotoxicity of PFOS, for which multi-omics and integrated omics analyses are efficient for discovering the significant molecular pathways related to developmental neurotoxicity in zebrafish.


How social and non-social information influence classification decisions: A computational modelling approach.
Social information such as observing others can improve performance in decision making. In particular, social information has been shown to be useful when finding the best solution on one's own is difficult, costly, or dangerous. However, past research suggests that when making decisions people do not always consider other people's behaviour when it is at odds with their own experiences. Furthermore, the cognitive processes guiding the integration of social information with individual experiences are still under debate. Here, we conducted two experiments to test whether information about other persons' behaviour influenced people's decisions in a classification task. Furthermore, we examined how social information is integrated with individual learning experiences by testing different computational models. Our results show that social information had a small but reliable influence on people's classifications. The best computational model suggests that in categorization people first make up their own mind based on the non-social information, which is then updated by the social information.


An overview of clinical trials of low molecular weight heparin fractions.
There is experimental evidence that low molecular weight heparin fractions are as effective as standard unfractionated heparin but cause less bleeding. In order to determine the efficacy and safety of low molecular weight heparins, we have conducted an overview of published randomized trials in which a low molecular weight heparin was compared to either placebo or to unfractionated heparin. In the two trials comparing low molecular weight heparin prophylaxis with placebo, the incidence of leg vein thrombosis was substantially reduced with low molecular weight heparin and there was no increased bleeding risk. There have been five trials which compared low molecular weight heparin with unfractionated heparin in high risk surgical patients. In one of these studies there was a statistically significant reduction in postoperative venous thrombosis in patients who received the low molecular weight heparin. In the remaining studies, thrombosis rates were relatively low in all groups and no difference was detected between low molecular weight heparin and unfractionated heparin. We found a significant relationship between ex vivo anti-factor Xa levels and clinically important bleeding, r = 0.54. We conclude that low molecular weight heparin is an effective method of prophylaxis and has a negligible risk of bleeding provided that the anti-factor Xa levels do not exceed 0.2 units per ml. There have been only three published randomized trials on the efficacy of low molecular weight heparin in the treatment of venous thrombosis. Much larger studies are required to establish the efficacy and safety of low molecular weight heparin fractions in the treatment of established venous thromboembolism.


First Report of Tomato mosaic virus on Hibiscus rosa-sinensis in China.
Hibiscus rosa-sinensis Linn., family Malvaceae, is an attractive horticultural plant originating from China. Five viruses infecting H. rosa-sinensis that have been characterized previously are Hibiscus chlorotic ringspot virus (HCRSV, genus Carmovirus), Hibiscus latent ringspot virus (HLRSV, genus Nepovirus), Hibiscus yellow mosaic virus (genus Tobamovirus), Eggplant mottled dwarf virus (EMDV, genus Nucleorhabdovirus), and Okra mosaic virus (OkMV, genus Tymovirus) (2). Recently, two novel tobamoviruses infecting H. rosa-sinensis were characterized in Singapore and Florida (1). In this study, viral symptoms were observed on H. rosa-sinensis in Nanyang City in Henan Province, China. The systemic symptoms included dark and light green mosaic in young leaves, leaf puckering and malformation on older leaves, and significant stunting. Rod-shaped virus particles were isolated from H. rosa-sinensis expressing systemic symptoms. The virus was transmitted mechanically to 10 species from three families. Symptoms expressed on these plants included systemic leaf chlorosis and distortion on Lycopersicum esculentum, systemic mosaic on Capsicum annuum, Nicotiana tabacum, and Physalis floridana, and systemic chlorosis on Glycine max. N. tabacum-Xanthi nc and Datura stramonium were asymptomatic. The virus also produced chlorotic and necrotic local lesions on Chenopodium quinoa, C. amaranticolor, and C. murale. The virus was propagated in L. esculentum, N. tabacum, and P. floridana. Virions purified from systemically infected N. tabacum contained a single-stranded RNA of approximately 6.4 kb and a coat protein (CP) of approximately 17.6 kDa. The double-stranded RNA profile revealed a single band of approximately 6.4 kb. Sap extracted from virus-infected plants reacted positive with an antiserum prepared against Tobacco mosaic virus (TMV) using an antigen-coated plate enzyme-linked immunosorbent assay. The CP gene was amplified by reverse transcription-polymerase chain reaction with primers specific to Tomato mosaic virus (ToMV) and sequence data obtained from the resulting amplification product. The CP gene consisting of 159 amino acids (GenBank Accession No. AY313136) shared 99.37% identity with the ToMV Queensland isolate (GenBank Accession No. AF332868). On the basis of biology, serology, properties of virions, and the sequence of the CP gene, we conclude that the virus isolated from H. rosa-sinensis in China is Tomato mosaic virus(ToMV). References: (1) S. Adkins et al. Plant Dis. 87:1190, 2003. (2) M. H. V. van Regenmortel et al., eds. Virus Taxonomy. 7th Report of the ICTV, Academic Press, NY, 2000.


Diagnostic validity of different cephalometric analyses for assessment of the sagittal skeletal pattern.
Numerous cephalometric analyses have been proposed to diagnose the sagittal discrepancy of the craniofacial structures. This study aimed at evaluating the reliability and validity of different skeletal analyses for the identification of sagittal skeletal pattern. A total of 146 subjects (males = 77; females = 69; mean age = 23.6 ± 4.6 years) were included. The ANB angle, Wits appraisal, Beta angle, AB plane angle, Downs angle of convexity and W angle were used to assess the anteroposterior skeletal pattern on lateral cephalograms. The sample was classified into Class I, II and III groups as determined by the diagnostic results of majority of the parameters. The validity and reliability of the aforementioned analyses were determined using Kappa statistics, sensitivity and positive predictive value (PPV). A substantial agreement was present between ANB angle and the diagnosis made by the final group (k = 0.802). In the Class I group, Downs angle of convexity showed the highest sensitivity (0.968), whereas ANB showed the highest PPV (0.910). In the Class II group, ANB angle showed the highest sensitivity (0.928) and PPV (0.951). In the Class III group, the ANB angle, the Wits appraisal and the Beta angle showed the highest sensitivity (0.902), whereas the Downs angle of convexity and the ANB angle showed the highest PPV (1.00). The ANB angle was found to be the most valid and reliable indicator in all sagittal groups. Downs angle of convexity, Wits appraisal and Beta angle may be used as valid indicators to assess the Class III sagittal pattern.


Using "Mighty Mouse" to understand masticatory plasticity: myostatin-deficient mice and musculoskeletal function.
Knockout mice lacking myostatin (Mstn), a negative regulator of the growth of skeletal muscle, develop significant increases in the relative mass of masticatory muscles as well as the ability to generate higher maximal muscle forces. Wild-type and Mstn-deficient mice were compared to investigate the postnatal influence of elevated masticatory loads due to increased jaw-adductor and bite forces on the biomineralization of mandibular articular and cortical bone, the internal structure of the jaw joints, and the composition of temporomandibular joint (TMJ) articular cartilage. To provide an interspecific perspective on the long-term responses of mammalian jaw joints to altered loading conditions, the findings on mice were compared to similar data for growing rabbits subjected to long-term dietary manipulation. Statistically significant differences in joint proportions and bone mineral density between normal and Mstn-deficient mice, which are similar to those observed between rabbit loading cohorts, underscore the need for a comprehensive analysis of masticatory tissue plasticity vis-à-vis altered mechanical loads, one in which variation in external and internal structure are considered. Differences in the expression of proteoglycans and type-II collagen in TMJ articular cartilage between the mouse and rabbit comparisons suggest that the duration and magnitude of the loading stimulus will significantly affect patterns of adaptive and degradative responses. These data on mammals subjected to long-term loading conditions offer novel insights regarding variation in ontogeny, life history, and the ecomorphology of the feeding apparatus.


Health utilities lost and risk factors associated with HPV-induced diseases in men and women: the HPV Italian collaborative study group.
A complete economic evaluation requires accurate data concerning the resources used, outcomes, and utilities (patient's preferences) to properly value the cost utility of human papillomavirus (HPV) vaccination strategies. This study was designed to measure the utility loss in health states affected by a broad range of HPV-induced pathologies in both sexes in Italy. As a secondary objective, risk factors influencing the viral transmission and development of HPV infections were also investigated. Patients with a diagnosis of several HPV-induced pathologies including atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasia (CIN), cervical and anal-colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and anogenital warts (AWs) were evaluated. Utilities, quality of life, and risk factors were elicited using a standardized and computer-guided administration of time trade-off, European Quality of Life 5 Dimensions (EQ-5D), 3 levels, and risk factor questionnaires. Utilities were measured at 6 clinical research centers across Italy. A group of healthy subjects was used as a control. A mean number of 20 healthy subjects was used as a control for each pathology group. Overall, 600 respondents were eligible for analysis: 465 patients (mean [SD] age, 44.0 [16.3] years) and 135 controls (mean [SD] age, 44.0 [13.2] years). With the exception of anal and HNSCC cancer, no statistically significant differences were observed between case and control groups, in terms of either age or quality of life at the time of interview. The patients' perception of their health condition at baseline was equal to an EQ-5D score of 0.87 (0.22). The mean (SD) value of utilities associated with the HPV-induced pathologies corresponded to 0.83 (0.24), 0.78 (0.27), 0.83 (0.22), 0.81 (0.27), 0.58 (0.31), 0.51 (0.26), and 0.69 (0.30) for ASC-US, AWs, CIN 1 (mild), CIN 2-3 (moderate to severe), cervical cancer, anal cancer and HNSCC, respectively. Utility lost due to AWs was significantly higher in females compared with males (0.71 [0.29] vs 0.83 [0.25]; P = 0.018). Having >5 sexual partners increased the risk of acquiring HPV-induced infections as much as 2.52-fold (P = 0.004), whereas for smoking or the age at start of sexual activity younger than 18 years, the risk increased by ~1.62-fold (P = 0.034). High levels of education were associated with a statistically significant protective effect (P < 0.001). Risk factors and utilities elicited in this study can be used as part of future economic assessments of other HPV vaccination strategies, including an immunization program for preadolescents of both sexes in Italy.


Randomized non-invasive sham-controlled pilot trial of electroacupuncture for postpartum depression.
Postpartum depression affects 10-15% of mothers. Although acupuncture was efficacious for major depressive disorder in pregnancy and in women outside the perinatal period, there has been no randomized controlled study on the feasibility, tolerability, and efficacy of acupuncture for postpartum depression. This was a randomized, subject- and assessor-blind, parallel-group, sham-controlled trial. Twenty women within six months postpartum with DSM-IV-diagnosed major depressive disorder of mild severity, defined as a 17-item Hamilton Depression Rating Scale (HDRS(17)) score of 12 to 19, were randomly assigned to either electroacupuncture or non-invasive sham acupuncture two sessions weekly for four weeks. There was significant reduction in HDRS(17) score from baseline to 4-week posttreatment in both groups, with an effect size 1.4 and 1.8 for electroacupuncture and sham acupuncture, respectively. Improvement was observed as early as two weeks after commencing acupuncture. The response and remission rate in the electroacupuncture group at 4-week posttreatment was 33% and 44%, respectively; for the sham acupuncture group, it was 60% and 50%, respectively. There was no significant between-group difference in all outcome measures, including the HDRS(17), Edinburgh Postnatal Depression Scale, Hospital Anxiety and Depression Scale, Clinical Global Impression, and Sheehan Disability Scale. Treatment credibility, success of blinding, and adverse events were similar between groups. Small sample size and high attrition rate. No waiting list observation group. Both electroacupuncture and non-invasive sham acupuncture were effective for postpartum depression. Further studies utilizing larger sample size, better recruitment strategies, and home-based acupuncture treatment are warranted. Pilot Study on the Use of Acupuncture for Postpartum Depression; ClinicalTrials.gov Registration #NCT01178008; URL - http://clinicaltrials.gov/ct2/show/NCT01178008?term=postpartum+acupuncture&rank=1.


Transmission reflection anomaly in second-harmonic generation from a monolayer.
We show experimentally that in second-harmonic generation from a monolayer the radiation propagating in transmission and that in reflection can have very different magnitudes. The origin of this difference lies in destructive and constructive interference of the components of the nonlinear polarization that drive the field at the second-harmonic frequency.


Electronic search strategies to identify reports of cluster randomized trials in MEDLINE: low precision will improve with adherence to reporting standards.
Cluster randomized trials (CRTs) present unique methodological and ethical challenges. Researchers conducting systematic reviews of CRTs (e.g., addressing methodological or ethical issues) require efficient electronic search strategies (filters or hedges) to identify trials in electronic databases such as MEDLINE. According to the CONSORT statement extension to CRTs, the clustered design should be clearly identified in titles or abstracts; however, variability in terminology may make electronic identification challenging. Our objectives were to (a) evaluate sensitivity ("recall") and precision of a well-known electronic search strategy ("randomized controlled trial" as publication type) with respect to identifying CRTs, (b) evaluate the feasibility of new search strategies targeted specifically at CRTs, and (c) determine whether CRTs are appropriately identified in titles or abstracts of reports and whether there has been improvement over time. We manually examined a wide range of health journals to identify a gold standard set of CRTs. Search strategies were evaluated against the gold standard set, as well as an independent set of CRTs included in previous systematic reviews. The existing strategy (randomized controlled trial.pt) is sensitive (93.8%) for identifying CRTs, but has relatively low precision (9%, number needed to read 11); the number needed to read can be halved to 5 (precision 18.4%) by combining with cluster design-related terms using the Boolean operator AND; combining with the Boolean operator OR maximizes sensitivity (99.4%) but would require 28.6 citations read to identify one CRT. Only about 50% of CRTs are clearly identified as cluster randomized in titles or abstracts; approximately 25% can be identified based on the reported units of randomization but are not amenable to electronic searching; the remaining 25% cannot be identified except through manual inspection of the full-text article. The proportion of trials clearly identified has increased from 28% between the years 2000-2003, to 60% between 2004-2007 (absolute increase 32%, 95% CI 17 to 47%). CRTs should include the phrase "cluster randomized trial" in titles or abstracts; this will facilitate more accurate indexing of the publication type by reviewers at the National Library of Medicine, and efficient textword retrieval of the subset employing cluster randomization.


Construction and analysis of a semi-quantitative energy profile for the reaction catalyzed by the radical enzyme galactose oxidase.
Galactose oxidase (GOase) is a mononuclear type 2 copper enzyme which oxidizes primary alcohols to aldehydes using molecular oxygen (RCH2OH + O2 = RCHO + H2O2). An unusual crosslink between tyrosine 272 and cysteine 228 provides a modified tyrosine radical site which acts as a ligand for the active site copper and is believed to act as a one-electron redox center. The single active site copper is believed to act as a second one-electron redox center. The use of the tyrosine one-electron redox center and the copper one-electron redox center allows removal of two electrons from alcohol substrate for subsequent transfer to molecular oxygen. Previously, we and others have proposed a detailed step-by-step radical mechanism for the reaction catalyzed by galactose oxidase. The catalytic cycle can be divided into two half reactions. The first half reaction entails transfer of two electrons and two protons from the alcohol substrate to the enzyme to form aldehyde product and two-electron-reduced enzyme (one electron at the tyrosine center and one at the copper center). The second half reaction entails transfer of two electrons and two protons from the two-electron-reduced enzyme to O2 to form H2O2 product and regenerate fully oxidized catalytically active enzyme ready for another catalytic cycle. In this paper, we describe the construction of a semi-quantitative energy profile for this radical mechanism. Several significant points emerge from this analysis. One point is the prediction that galactose oxidase should have an unusually low redox potential for copper, to our knowledge lower than any other redox active copper protein. Another point is that the distorted or entatic copper site causes the unusually low redox potential. A final point is that crosslinking of tyrosine 272 and cysteine 228 alters the redox properties of the tyrosine center to enhance catalysis compared to what would be expected for a normal tyrosine.


Wanted: a better cut-off value for the Epworth Sleepiness Scale.
Excessive daytime sleepiness (EDS) is the main complaint in many neurological sleep disorders, such as idiopathic hypersomnia, narcolepsy, or obstructive sleep apnea/hypopnea syndrome (OSAS). The validity of the Epworth Sleepiness Scale (ESS) as a screening tool for EDS remains controversial. We therefore investigated (1) the interrelation of the ESS total score and the mean sleep latency (MSL) during the multiple sleep latency test (MSLT) and (2) the diagnostic accuracy of the ESS total score to detect EDS in patients with the chief complaint of subjective EDS. A total of 94 patients (48 males) with subjective EDS were included in this study. Regression analyses and ROC curve analyses were carried out to assess the predictive value of the ESS score for MSL. The ESS score significantly predicted a shortened MSL (p = 0.01, β = -0.29). After dichotomizing into two groups, the ESS score predicted MSL only in patients with hypersomnia or narcolepsy (p = 0.01, β = -0.33), but not in patients with other clinical diagnoses (e. g. OSAS; p = 0.36, β = -0.15). The ROC curve analyses indicated an optimal ESS cut-off value of 16 with a sensitivity of 70%; however, specificity remained unsatisfactory (55.6%). Our results suggest that the predictive value of the ESS score in patients with subjective EDS is low and patient subgroup-specific (superior in hypersomnia/narcolepsy vs. other diagnoses) and that the commonly used cut-off of 11 points may be insufficient for clinical practice.


A qualitative study: professionals' experiences of advance care planning in dementia and palliative care, 'a good idea in theory but ...'.
Advance care planning comprises discussions about an individual's wishes for future care while they have capacity. To explore professionals' experiences on the implementation of advance care planning in two areas of clinical care, dementia and palliative care. Qualitative study, focus groups and individual interviews. North East of England. Ninety-five participants from one Primary Care Trust, two acute National Health Service Hospital Trusts, one Ambulance Trust, one Local Authority and voluntary organisations and the legal sector. Fourteen focus groups and 18 interviews were held with 95 participants. While professionals agreed that advance care planning was a good idea in theory, implementation in practice presented them with significant challenges. The majority expressed uncertainty over the general value of advance care planning, whether current service provision could meet patient wishes, their individual roles and responsibilities and which aspects of advance care planning were legally binding; the array of different advance care planning forms and documentation available added to the confusion. In dementia care, the timing of when to initiate advance care planning discussions was an added challenge. This study has identified the professional, organisational and legal factors that influence advance care planning implementation; professional training should target these specific areas. There is an urgent need for standardisation of advance care planning documentation. Greater clarity is also required on the roles and responsibilities of different professional groups. More complex aspects of advance care planning may be better carried out by those with specialist skills and experience than by generalists caring for a wide range of patient groups with different disease trajectories.


A comparison of English and French approaches to providing patients access to Summary Care Records: scope, consent, cost.
Online access to records is part of the process of empowering patients. National health services in both France and England have introduced systems to provide online access to summary health data. The English system was called the "Summary Care Record (SCR)," made accessible to patients through "HealthSpace". The French system Dossier Médical Personnel (DMP) is a patient controlled record clinicians enter data into. The objective was to compare the programmes and lessons from the introduction of patient access. We carried out a literature review. The English system has been progressively de-scoped, with HealthSpace due to close in 2013, only 0.01% of the population signing up for "advanced accounts". The French system slowly grows as more documents are added; though only 0.31% of the population have opened a DMP. The English SCR has an opt-out consent model, whereas the French DMP is patient controlled opt-in consent model. The SCR sits within an NHS intranet while the DMP sits on the Internet. Both systems have costs of around 200 million Euro. Providing patients online access to their medical records is potentially empowering. However, the English HealthSpace and SCR have failed to deliver and are due to be withdrawn as methods of providing patients online access. The French system is still in operation but much criticized for its high costs and low uptake. The design of these systems does not appear to have met patients' needs or been readily integrated into physicians workflow.


Changing the South African national antiretroviral therapy guidelines: The role of cost modelling.
We were tasked by the South African Department of Health to assess the cost implications to the largest ART programme in the world of adopting sets of ART guidelines issued by the World Health Organization between 2010 and 2016. Using data from large South African ART clinics (n = 24,244 patients), projections of patients in need of ART, and cost data from bottom-up cost analyses, we constructed a population-level health-state transition model with 6-monthly transitions between health states depending on patients' age, CD4 cell count/ percentage, and, for adult first-line ART, time on treatment. For each set of guidelines, the modelled increase in patient numbers as a result of prevalence and uptake was substantially more than the increase resulting from additional eligibility. Under each set of guidelines, the number of people on ART was projected to increase by 31-133% over the next seven years, and cost by 84-175%, while increased eligibility led to 1-26% more patients, and 1-17% higher cost. The projected increases in treatment cost due to the 2010 and the 2015 WHO guidelines could be offset in their entirety by the introduction of cost-saving measures such as opening the drug tenders for international competition and task-shifting. Under universal treatment, annual costs of the treatment programme will decrease for the first time from 2024 onwards. Annual budgetary requirements for ART will continue to increase in South Africa until universal treatment is taken to full scale. Model results were instrumental in changing South African ART guidelines, more than tripling the population on treatment between 2009 and 2017, and reducing the per-patient cost of treatment by 64%.


Transcriptome analysis reveals mucin 4 to be highly associated with periodontitis and identifies pleckstrin as a link to systemic diseases.
The multifactorial chronic inflammatory disease periodontitis, which is characterized by destruction of tooth-supporting tissues, has also been implicated as a risk factor for various systemic diseases. Although periodontitis has been studied extensively, neither disease-specific biomarkers nor therapeutic targets have been identified, nor its link with systemic diseases. Here, we analyzed the global transcriptome of periodontitis and compared its gene expression profile with those of other inflammatory conditions, including cardiovascular disease (CVD), rheumatoid arthritis (RA), and ulcerative colitis (UC). Gingival biopsies from 62 patients with periodontitis and 62 healthy subjects were subjected to RNA sequencing. The up-regulated genes in periodontitis were related to inflammation, wounding and defense response, and apoptosis, whereas down-regulated genes were related to extracellular matrix organization and structural support. The most highly up-regulated gene was mucin 4 (MUC4), and its protein product was confirmed to be over-expressed in periodontitis. When comparing the expression profile of periodontitis with other inflammatory diseases, several gene ontology categories, including inflammatory response, cell death, cell motion, and homeostatic processes, were identified as common to all diseases. Only one gene, pleckstrin (PLEK), was significantly overexpressed in periodontitis, CVD, RA, and UC, implicating this gene as an important networking link between these chronic inflammatory diseases.


Subclinical hyperthyroid patients' knowledge about radioiodine therapy--the key role of medical information.
Many patients with a chronic disease are dissatisfied with the information they are given. A brief questionnaire completed by patients would assist health professionals to identify areas of information needed to be provided, tailored to the patient's mental condition. The aim of our study was to assess how often thyroid patients report being adequately informed about iodine treatment in connection with their real need thereof, emotional state and acceptance of the disease. One hundred outpatients who had presented subclinical hyperthyroidism "[19 men (19%), 81 women (81%); mean (SD±) age 53±14,range 18-77 yr ] treated with radioiodine (RAI) responded to an Experimental Questionnaire, 54 of them answered to AIS, HADS-M and Beck Inventory measuring their acceptance of the illness and depressive symptoms, 37 of them answered the Patient Request Form (PRF). The obtained results indicated that about 50% of patients treated with 131I therapy did not receive suitable information about their treatment. Neither written information prepared by the specialist, nor verbal information given by physicians were adequate for specific problems of study group. The examined patients presented with a comparable intensity of three distinct types of requests: for explanation and reassurance, for emotional support, and for investigation and treatment. The acceptance of their disease was mediocre for most of the study group. We conclude that the reported lack of satisfaction with medical information in study group was associated with depressive symptoms influencing cognitive efficiency, patients' great need of emotional and cognitive support, influencing the acceptance of their disease, and social prejudice to radioiodine (as a method of treatment), worrying them additionally. All thyroid patients even these with subclinical symptoms of hyperthyroidism should be treated with specific attention by physicians, especially during information process.


Overall and health related quality of life among the oldest old in pain.
To compare the oldest old (85 years and above) in pain with those with no pain across gender, regarding demographic data, living conditions, social network/support, walking/mobility problems, fatigue, sleeping problems, depressed mood and quality of life (QoL). The aim was also to test how these variables were related to QoL among the oldest old in pain. The study comprised 1622 people aged 85-105 years, of whom 47% reported pain. SF-12 and the LGC questionnaire were used to measure QoL. Multiple linear regression analysis was used to identify factors associated with QoL. Functional limitations, fatigue, sleeping problem and depressed mood were significantly more prevalent and QoL was significantly lower among those in pain than those not in pain, and among women compared to men. These complaints, along with financial problems, living in sheltered housing and living alone, were associated with low QoL among those in pain. Pain is common among the oldest old and coexists with several other complaints that together negatively affect QoL. By identifying those in pain and coexisting factors, actions can be taken to contribute to QoL, also in late life.


Differential proteomic analysis of cyclosporine A-induced toxicity in renal proximal tubule cells.
The use of cyclosporine A (CsA) as a potent immunosuppressant has been limited by its severe nephrotoxic effects. The mechanisms involved are haemodynamic but also related to direct toxic effects of CsA on proximal tubule epithelial cells. We focused on defining a proteomic profile in CsA-treated proximal tubule cells to distinguish the direct impact of CsA on these cells from overlapping haemodynamically mediated phenomena that occur in an in vivo system. By means of high-throughput differential proteomic analyses and mass spectrometry techniques in CsA and vehicle-treated proximal tubule-derived cell lines of human and mouse origin, we determined proteins that change their expression in the presence of CsA. CsA-induced toxicity analyses revealed that 10 mM CsA for 24 h was the threshold condition to induce significant changes in cell viability and proteomic profile. We identified 38 differentially expressed proteins on CsA-treated mouse PCT3 and human HK-2 cells, related to protein metabolism, response to damage, cell organization and cytoskeleton, energy metabolism, cell cycle and nucleobase/nucleoside/nucleotidic metabolism. 1D and 2D western blot assays in crude extracts from CsA-treated cells or kidneys with impaired function upon CsA treatment revealed a correlation with proteomic changes or differential isoform expression, in randomly selected proteins. Proteins identified in this work might be useful markers to eventually distinguish CsA toxicity from chronic allograft nephropathy in protocol biopsies of transplanted patients, facilitating the adjustment of CsA doses to non-toxic ranges, as well as to study the impact of potential therapeutic interventions in an animal model.


Comparison of spectrolyser device measurements with standard analysis of wastewater samples in Novi Sad, Serbia.
On-line monitoring was performed using spectrolyser equipment, coupled with laboratory analysis for samples collected from wastewater discharge in the city of Novi Sad, Serbia, during first 24 h of three and 48 h of six monitoring campaigns from December of 2012 to April of 2013. Significant correlation with R(2) > 0.9 was observed between laboratory analysis and spectrolyser measurements for chemical oxygen demand (COD) and biological oxygen demand (BOD) concentrations. COD/BOD5 ratio in combined industrial and municipal wastewater ranged from 1.2 to 2.0 indicating the presence of biodegradable organic matter which could be easily removed using aeration treatment process. Micro/trace element and/or heavy metals in wastewater samples were within the limits as per the standard prescribed for wastewater, and should not pose any serious hazard risk. However BOD, COD, ammonia and total phosphorus concentrations were measured above the limit value according to Serbian and EU legislation and should be reduced before discharging wastewater directly into the Danube River.


Predictors of injury-related and non-injury-related mortality among veterans with alcohol use disorders.
To describe the association between alcohol use disorders (AUDs) and mortality and to examine risk factors for and all-cause, injury-related and non-injury-related mortality among those diagnosed with an AUD. Department of Veterans Affairs, Veterans Health Administration (VHA). A cohort of individuals who received health care in VHA during the fiscal year (FY) 2001 (n = 3,944,778), followed from the beginning of FY02 through the end of FY06. Demographics and medical diagnoses were obtained from VHA records. Data on mortality were obtained from the National Death Index. Controlling for age, gender and race and compared to those without AUDs, individuals with AUDs were more likely to die by all causes [hazard ratio (HR) = 2.30], by injury-related (HR = 3.29) and by non-injury-related causes (HR = 2.21). Patients with AUDs died 15 years earlier than individuals without AUDs on average. Among those with AUDs, Caucasian ethnicity and all mental illness diagnoses that were assessed were associated more strongly with injury-related than non-injury-related mortality. Also among those with AUDs, individuals with medical comorbidity and older age were at higher risk for non-injury related compared to injury-related mortality. In users of a large health-care system, a diagnosis of an AUD is associated significantly with increased likelihood of dying by injury and non-injury causes. Patients with a diagnosis of an AUD who die from injury differ significantly from those who die from other medical conditions. Prevention and intervention programs could focus separately upon selected groups with increased risk for injury or non-injury-related death.


Limited Engagements? Women's and Men's Work/Volunteer Time in the Encore Life Course Stage.
Americans are living healthier and longer lives, but the shifting age distribution is straining existing and projected social welfare protections for older adults (e.g., Social Security, Medicare). One solution is to delay retirement. Another is an alternative to "total leisure" retirement -- an "encore" stage of paid or unpaid engagement coming after career jobs but before infirmities associated with old age. We draw on gendered life-course themes together with data from the American Time Use Survey (2003-2009) to examine the real time American men and women ages 50-75 apportion to paid work and unpaid volunteer work on an average day, as well as factors predicting their time allocations. We find that while full-time employment declines after the 50s, many Americans allot time to more limited engagements - working part time, being self-employed, volunteering, helping out - through and even beyond their 60s. Caring for a child or infirm adult reduces the odds of paid work but not volunteering. While time working for pay declines with age (though more slowly for men than women), time volunteering does not. Older men and women in poor health, without a college degree, with a disability or SSI income are the least likely to be publicly engaged. This social patterning illustrates that while the ideal of an encore of paid or unpaid voluntary, flexible, and meaningful engagement is an emerging reality for some, it appears less attainable for others. This suggests the importance of organizational and public policy innovations offering all Americans a range of encore opportunities.


Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection.
Multi-parent populations (MPPs) capture and maintain the genetic diversity from multiple inbred founder strains to provide a resource for high-resolution genetic mapping through the accumulation of recombination events over many generations. Breeding designs that maintain a large effective population size with randomized assignment of breeders at each generation can minimize the impact of selection, inbreeding, and genetic drift on allele frequencies. Small deviations from expected allele frequencies will have little effect on the power and precision of genetic analysis, but a major distortion could result in reduced power and loss of important functional alleles. We detected strong transmission ratio distortion in the Diversity Outbred (DO) mouse population on chromosome 2, caused by meiotic drive favoring transmission of the WSB/EiJ allele at the R2d2 locus. The distorted region harbors thousands of polymorphisms derived from the seven non-WSB founder strains and many of these would be lost if the sweep was allowed to continue. To ensure the utility of the DO population to study genetic variation on chromosome 2, we performed an artificial selection against WSB/EiJ alleles at the R2d2 locus. Here, we report that we have purged the WSB/EiJ allele from the drive locus while preserving WSB/EiJ alleles in the flanking regions. We observed minimal disruption to allele frequencies across the rest of the autosomal genome. However, there was a shift in haplotype frequencies of the mitochondrial genome and an increase in the rate of an unusual sex chromosome aneuploidy. The DO population has been restored to genome-wide utility for genetic analysis, but our experience underscores that vigilant monitoring of similar genetic resource populations is needed to ensure their long-term utility.


The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management.
Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint-related endocrinopathies.


Co-occurrence of extremes in surface ozone, particulate matter, and temperature over eastern North America.
Heat waves and air pollution episodes pose a serious threat to human health and may worsen under future climate change. In this paper, we use 15 years (1999-2013) of commensurately gridded (1° x 1°) surface observations of extended summer (April-September) surface ozone (O3), fine particulate matter (PM2.5), and maximum temperature (TX) over the eastern United States and Canada to construct a climatology of the coincidence, overlap, and lag in space and time of their extremes. Extremes of each quantity are defined climatologically at each grid cell as the 50 d with the highest values in three 5-y windows (∼95th percentile). Any two extremes occur on the same day in the same grid cell more than 50% of the time in the northeastern United States, but on a domain average, co-occurrence is approximately 30%. Although not exactly co-occurring, many of these extremes show connectedness with consistent offsets in space and in time, which often defy traditional mechanistic explanations. All three extremes occur primarily in large-scale, multiday, spatially connected episodes with scales of >1,000 km and clearly coincide with large-scale meteorological features. The largest, longest-lived episodes have the highest incidence of co-occurrence and contain extreme values well above their local 95th percentile threshold, by +7 ppb for O3, +6 µg m-3 for PM2.5, and +1.7 °C for TX. Our results demonstrate the need to evaluate these extremes as synergistic costressors to accurately quantify their impacts on human health.


Perip7lakin is a target for autoimmunity in asthma.
The role of autoimmunity targeting epithelial antigens in asthma has been suggested, in particular in non-atopic and severe asthma. Periplakin, a desmosomal component, is involved in epithelial cohesion and intracellular signaling. We detected anti-periplakin IgG antibodies in 47/260 (18 %) patients with asthma, with no association with severity or atopy. In addition, anti-periplakin IgE antibodies were detected in 12 of 138 tested patients (8.7 %) and were more frequently observed in patients with than without nasal polyposis. This study identifies a new autoimmune epithelial target in asthma. Whether periplakin autoimmunity (both IgG and IgE auto-antibodies) is involved in asthma pathogenesis remains to be studied during the disease course of these patients.


Safety and efficacy of ticlopidine for only 2 weeks after successful intracoronary stent placement.
In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis. We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64+/-11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3+/-0.5 mm. High-pressure inflations (>/=12 atm) were performed in all patients (mean, 17+/-4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%. In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.


Cirrhotic Ascites management via procalcitonin level and a new approach B-mode gray-scale histogram.
To determine the role of serum procalcitonin levels and ascites/subcutaneous echogenicity ratio (ASER) in predicting ascites infection in hospitalized cirrhotic patients. A total of 50 patients hospitalized because of cirrhosis-related ascites were included in this study. In these patients, 44% of ascites were infected (peritonitis), whereas 56% of ascites were sterile. These two groups were compared in terms of procalcitonin levels and ASER for predicting ascites infection. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of ASER, and the predicting outcome of ASER was compared with procalcitonin levels. The ASER values of the patients with the diagnosis of infected ascites were significantly higher than in those with the diagnosis of sterile ascites (p<0.001). ROC analysis was performed to determine the diagnostic ASER value for infected ascites. An ASER greater than 0.0019 determined peritonitis with 95.5% sensitivity and 100% specificity. A procalcitonin level greater than 0.05 determined peritonitis with 86.4% sensitivity and 75% specificity. Using ROC analysis, an ASER greater than 0.0019 [area under curve (AUC): 0.974, 95% confidence interval (CI) (0.884-0.999, p<0.001)] was a significantly better diagnostic marker than a procalcitonin level >0.5 mg/dL [AUC: 0.860, 95% CI (0.884-0.999, p<0.001) (p<0.045)]. According to our findings, the determination of ASER and serum procalcitonin levels seems to provide satisfactory diagnostic accuracy in differentiating ascites infections in hospitalized cirrhotic patients. ASER values significantly differentiate ascites infections better than procalcitonin levels.


Resuscitation Education Science: Educational Strategies to Improve Outcomes From Cardiac Arrest: A Scientific Statement From the American Heart Association.
The formula for survival in resuscitation describes educational efficiency and local implementation as key determinants in survival after cardiac arrest. Current educational offerings in the form of standardized online and face-to-face courses are falling short, with providers demonstrating a decay of skills over time. This translates to suboptimal clinical care and poor survival outcomes from cardiac arrest. In many institutions, guidelines taught in courses are not thoughtfully implemented in the clinical environment. A current synthesis of the evidence supporting best educational and knowledge translation strategies in resuscitation is lacking. In this American Heart Association scientific statement, we provide a review of the literature describing key elements of educational efficiency and local implementation, including mastery learning and deliberate practice, spaced practice, contextual learning, feedback and debriefing, assessment, innovative educational strategies, faculty development, and knowledge translation and implementation. For each topic, we provide suggestions for improving provider performance that may ultimately optimize patient outcomes from cardiac arrest.