Prediction and classification of protein subcellular location-sequence-order effect and pseudo amino acid composition.
Given a protein sequence, how to identify its subcellular location? With the rapid increase in newly found protein sequences entering into databanks, the problem has become more and more important because the function of a protein is closely correlated with its localization. To practically deal with the challenge, a dataset has been established that allows the identification performed among the following 14 subcellular locations: (1) cell wall, (2) centriole, (3) chloroplast, (4) cytoplasm, (5) cytoskeleton, (6) endoplasmic reticulum, (7) extracellular, (8) Golgi apparatus, (9) lysosome, (10) mitochondria, (11) nucleus, (12) peroxisome, (13) plasma membrane, and (14) vacuole. Compared with the datasets constructed by the previous investigators, the current one represents the largest in the scope of localizations covered, and hence many proteins which were totally out of picture in the previous treatments, can now be investigated. Meanwhile, to enhance the potential and flexibility in taking into account the sequence-order effect, the series-mode pseudo-amino-acid-composition has been introduced as a representation for a protein. High success rates are obtained by the re-substitution test, jackknife test, and independent dataset test, respectively. It is anticipated that the current automated method can be developed to a high throughput tool for practical usage in both basic research and pharmaceutical industry.


Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation.
Increasing awareness of the importance of cardiovascular prevention is not yet matched by the resources and actions within health care systems. Recent publication of the European Commission's European Heart Health Charter in 2008 prompts a review of the role of cardiac rehabilitation (CR) to cardiovascular health outcomes. Secondary prevention through exercise-based CR is the intervention with the best scientific evidence to contribute to decrease morbidity and mortality in coronary artery disease, in particular after myocardial infarction but also incorporating cardiac interventions and chronic stable heart failure. The present position paper aims to provide the practical recommendations on the core components and goals of CR intervention in different cardiovascular conditions, to assist in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and consumers in the recognition of the comprehensive nature of CR. Those charged with responsibility for secondary prevention of cardiovascular disease, whether at European, national or individual centre level, need to consider where and how structured programmes of CR can be delivered to all patients eligible. Thus a novel, disease-oriented document has been generated, where all components of CR for cardiovascular conditions have been revised, presenting both well-established and controversial aspects. A general table applicable to all cardiovascular conditions and specific tables for each clinical disease have been created and commented.


Healthcare-associated outbreaks and community-acquired infections due to MRSA carrying the Panton-Valentine leucocidin gene in southeastern Germany.
In response to several isolations of methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leucocidin gene (PVL-MRSA), the present study was conducted to document the spread of infection in a small region of southeastern Germany. During a 9-month period, two healthcare-associated outbreaks with PVL-MRSA occurred, affecting 83 patients, personnel and contacts of personnel, and 34 additional cases were detected in the community. The clinical spectrum ranged from colonization to skin infection and necrotizing pneumonia. The findings represent the largest number of PVL-MRSA cases detected in Germany so far, and demonstrate the potential of this emerging pathogen to spread within the community and in healthcare institutions.


Community-based misoprostol for the prevention of post-partum haemorrhage: A narrative review of the evidence base, challenges and scale-up.
Achieving Sustainable Development Goal targets for 2030 will require persistent investment and creativity in improving access to quality health services, including skilled attendance at birth and access to emergency obstetric care. Community-based misoprostol has been extensively studied and recently endorsed by the WHO for the prevention of post-partum haemorrhage. There remains little consolidated information about experience with implementation and scale-up to date. This narrative review of the literature aimed to identify the political processes leading to WHO endorsement of misoprostol for the prevention of post-partum haemorrhage and describe ongoing challenges to the uptake and scale-up at both policy and community levels. We review the peer-reviewed and grey literature on expansion and scale-up and present the issues central to moving forward.


Interleukin-17A Exacerbates Ferric Chloride-Induced Arterial Thrombosis in Rat Carotid Artery.
Interleukin-17A (IL-17A), the most widely studied member of the IL-17 cytokine family, is a cytokine which emerged to be critical for host defense as well as in the pathogenesis of autoimmune disorders. Moreover, IL-17A is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis and acute coronary syndrome and in the cardiovascular risk associated with systemic immunological disorders. Consistent with this, we have recently shown that IL-17A increases human and murine platelet response to ADP. In this study we expanded our previous observation and we describe for the first time an in vivo prothrombotic effect of the cytokine. Our results show that IL-17A is synergic with a low FeCl3 concentration in inducing carotid thrombus in rats and suggest that the effect is likely related to a downregulation of CD39 vascular expression and hydrolyzing activity. Our findings indicate that IL-17A might be an important molecule at the interface between hemostasis and inflammation. "This paper is dedicated to the memory of Professor Alfredo Colonna"


Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans.
Plasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans. We performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log10 kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry. Among 597 Ugandans, 62% were woman, median age was 35, median baseline CD4 cell count was 135 cells/μl, and median baseline HIV-1 RNA was 5.1 log10 copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10 kynurenine/tryptophan ratio (P < 5.0 × 10). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 × 10), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (N = 262; 33% African-American). Our findings highlight a potentially important role of IFN-γ, TNF-α, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations.


Differential effect of sinefungin and its analogs on the multiplication of three Leishmania species.
Sinefungin and seven analogs were evaluated in vitro for activity against promastigote multiplication of Leishmania donovani, L. tropica, and L. enrietti. Of these compounds, sinefungin, the cyclic derivative, and A9145C were leishmanicidal at concentrations ranging from 0.13 to 2.6 microM. Sinefungin was the most active of these three compounds against L. donovani, and A9145C was most active against L. enrietti. None of the remaining derivatives exhibited significant activity against any one of the three species at the highest dose tested. All agents were assayed for activity against protein methylases I and III. The results of these tests showed that there is no relationship between the inhibition of growth and inhibition of protein methylases I and III.


Characteristics of the indirect McCollough effect.
Induction of contingent color aftereffects with a single chromatic grid sometimes results in an illusory color on a grid different from the one presented during induction. Such illusory color, contingently elicited by a noninduced grid, has been termed the indirect McCollough effect (indirect ME). We show that the indirect ME occurs only when the color complementary to the grid color is present during induction (either physically present or as a color afterimage), and that the indirect ME is seen only on gratings that are orthogonal to the induction orientation. These findings are in accord with the account of the indirect ME proposed by Humphrey, Dodwell, and Emerson (1989). We also show that characteristics of the indirect ME (seen following one-grid induction), both on induced and orthogonal orientations, are similar to those observed with the direct ME (seen following the usual two-grid induction procedure). Both procedures result in contingent aftereffects that display substantial retention and that do not display interocular transfer.


[Children's games; observations and experiences].
In contrast with free play, children's rule-governed game playing has raised little interest among psychodynamic investigators. It is generally assumed that games such as hopscotch, marbles, tag and ball games--because of their fixed rules--leave little room for personal fantasy or creative enterprise, which often characterise free play. A partial self-analysis of replaying-in-mind of a childhood game is presented, in order to demonstrate the essential functions of rules in the unconscious fantasies enacted in such games, and regressive, as well as maturational functions thus served. The analysis presented also reveals that games that are dictated by strict rules, nevertheless offer a wide scope for creative enterprise since any game, just like, e.g., a piece of music, may be performed with great virtuosity without breaking any rules. It is argued that the use of reconstruction-in-mind of childhood game experiences--when one can open up to the child within and relive these experiences--is a method of investigation that may be fruitfully added to the traditional ones. The insights reached by means of this method were not as accesible through analysis of data obtained in earlier research, conducted by other means, namely, observations and recordings of children at play, as well as interviews with children.


In silico identification of irreversible cathepsin B inhibitors as anti- cancer agents: virtual screening, covalent docking analysis and molecular dynamics simulations.
Cathepsin B is a cysteine protease that belongs to the papain superfamily. Malfunctions related to cathepsin B can lead to inflammation and cancer. Via an integrated in silico approach, this study is aimed to identify novel Michael acceptors-type compounds that can irreversibly inhibit cathepsin B enzyme via covalent bond formation with the active site cysteine residue. Here, we report the first account of covalent docking approach incorporated into a hybrid ligand/structure-based virtual screening to estimate the binding affinities of various compounds from chemical databases against the cathepsin B protein. For validation, compounds with experimentally determined anti-cathepsin B activity from PubChem bioassay database were also screened and covalently docked to the enzyme target. Interestingly, four novel compounds exhibited better covalent binding affinity when compared against the experimentally determined prototypes. Molecular dynamics simulations were performed to ensure the stability of the docked complexes and to allow further analysis on the MD average structures. Perresidue interaction decomposition analysis was carried out to provide deeper insight into the interaction themes of discovered hits with the active site residues. It is found that polar and hydrophobic interactions contributed the most towards drug binding. The hybrid computational methods applied in this study should serve as a powerful tool in the drug design and development process.


The psychometric network structure of mental health in eating disorder patients.
Psychometric network analysis has led to new possibilities to assess the structure and dynamics of psychiatric disorders. The current study focuses on mental health networks in patients with anorexia nervosa, bulimia nervosa, binge eating disorder and other specified eating disorders (EDs). Network analyses were applied with five mental health domains (emotional, psychological and social well-being, and general and specific psychopathology) among 905 ED patients. Also, networks of 36 underlying symptoms related to the domains were estimated. The network stability, structure and (bridge) centrality of the nodes were assessed for the total group and each ED type. Network differences between the ED types were also examined. ED psychopathology was only weakly connected with the well-being domains. Psychological well-being was the most central node in the domain network. The most central nodes in the symptom network were feeling depressed, feeling worthless, purpose in life and self-acceptance. Bridge symptoms between well-being and psychopathology were self-acceptance, environmental mastery, interested in life and feeling depressed. There were no network differences between the ED types in both the domain and symptom networks. This study shows novel associations between well-being and psychopathology in ED patients. Central domains and their underlying symptoms may be especially important to consider in treatment for promoting mental health in ED patients.


Interplay between DNA methylation and transcription factor availability: implications for developmental activation of the mouse Myogenin gene.
During development, gene activation is stringently regulated to restrict expression only to the correct cell type and correct developmental stage. Here, we present mechanistic evidence that suggests DNA methylation contributes to this regulation by suppressing premature gene activation. Using the mouse Myogenin promoter as an example of the weak CpG island class of promoters, we find that it is initially methylated but becomes demethylated as development proceeds. Full hypersensitive site formation of the Myogenin promoter requires both the MEF2 and SIX binding sites, but binding to only one site can trigger the partial chromatin opening of the nonmethylated promoter. DNA methylation markedly decreases hypersensitive site formation that now occurs at a detectable level only when binding to both MEF2 and SIX binding sites is possible. This suggests that the probability of activating the methylated promoter is low until two of the factors are coexpressed within the same cell. Consistent with this, the single-cell analysis of developing somites shows that the coexpression of MEF2A and SIX1, which bind the MEF2 and SIX sites, correlates with the fraction of cells that demethylate the Myogenin promoter. Taken together, these studies imply that DNA methylation helps to prevent inappropriate gene activation until sufficient activating factors are coexpressed.


On uncertain sightings and inference about extinction.
The extinction of many species can only be inferred from the record of sightings of individuals. Solow et al. (2012, Uncertain sightings and the extinction of the Ivory-billed Woodpecker. Conservation Biology 26:180-184) describe a Bayesian approach to such inference and apply it to a sighting record of the Ivory-billed Woodpecker (Campephilus principalis). A feature of this sighting record is that all uncertain sightings occurred after the most recent certain sighting. However, this appears to be an artifact. We extended this earlier work in 2 ways. First, we allowed for overlap in time between certain and uncertain sightings. Second, we considered 2 plausible statistical models of a sighting record. In one of these models, certain and uncertain sightings that are valid arise from the same process whereas in the other they arise from independent processes. We applied both models to the case of the Ivory-billed Woodpecker. The result from the first model did not favor extinction, whereas the result for the second model did. This underscores the importance, in applying tests for extinction, of understanding what could be called the natural history of the sighting record.


Stability of spin-orbit coupled Fermi gases with population imbalance.
We use the self-consistent mean-field theory to analyze the effects of Rashba-type spin-orbit coupling (SOC) on the ground-state phase diagram of population-imbalanced Fermi gases throughout the BCS-Bose-Einstein condensate evolution. We find that the SOC and population imbalance are counteracting, and that this competition tends to stabilize the uniform superfluid phase against the phase separation. However, we also show that the SOC stabilizes (destabilizes) the uniform superfluid phase against the normal phase for low (high) population imbalances. In addition, we find topological quantum phase transitions associated with the appearance of momentum-space regions with zero quasiparticle energies, and study their signatures in the momentum distribution.


Oropharyngeal morphology in the basal tortoise Manouria emys emys with comments on form and function of the testudinid tongue.
In tetrapods, the ability to ingest food on land is based on certain morphological features of the oropharynx in general and the feeding apparatus in particular. Recent paleoecological studies imply that terrestrial feeding has evolved secondarily in turtles, so they had to meet the morphological oropharyngeal requirements independently to other amniotes. This study is designed to improve our limited knowledge about the oropharyngeal morphology of tortoises by analyzing in detail the oropharynx in Manouria emys emys. Special emphasis is placed on the form and function of the tongue. Even if Manouria is considered a basal member of the only terrestrial turtle clade and was hypothesized to have retained some features reflecting an aquatic ancestry, Manouria shows oropharyngeal characteristics found in more derived testudinids. Accordingly, the oropharyngeal cavity in Manouria is richly structured and the glands are large and complexly organized. The tongue is large and fleshy and bears numerous slender papillae lacking lingual muscles. The hyolingual skeleton is mainly cartilaginous, and the enlarged anterior elements support the tongue and provide insertion sides for the well-developed lingual muscles, which show striking differences to other reptiles. We conclude that the oropharyngeal design in Manouria differs clearly from semiaquatic and aquatic turtles, as well as from other reptilian sauropsids.


Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.
Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated. To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers). All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation. A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation. Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.


Neurodevelopmental outcome at early school age in a Swiss national cohort of very preterm children.
Infants born very preterm are at higher risk of long-term neurodevelopmental problems than children born at term. Although there are increasing numbers of reports on outcomes from international cohorts of premature infants, a Swiss national report on infants after 2 years of age is lacking. To describe neurodevelopmental outcomes at early school age of preterm children born in Switzerland with a special focus on the cognitive abilities. This prospective national cohort study included children born alive before 30 weeks of gestation in 2006. At 5 years of age, children underwent a neurological examination and intelligence testing with the Kaufman Assessment Battery for Children first edition (K-ABC). We assessed the mental processing composite score (MPC) and its subscales to explore specific cognitive deficits. The primary outcome was cognitive impairment (MPC score <-1 standard deviation from the normative mean), motor impairment (cerebral palsy), or sensory impairment (any visual or hearing deficiency). The need for early intervention or therapies and the association of perinatal factors with cognitive impairment were secondary and tertiary outcomes. Logistic regression models were used to analyse associations between neonatal factors and cognitive outcome. Of 289 survivors, 235 were assessed. Of the 199 children with results obtained from the K-ABC, 42 (21%) showed cognitive impairment and 80 (40%) showed impairment in short-term memory. Cerebral palsy was diagnosed in 14 (6%), and visual and auditory impairment in 36 (15%) and 12 (5%) children, respectively; 63 (27%) needed early intervention or therapies. Cognitive impairment was associated with low socioeconomic status, but not with gestational age, small birthweight for gestational age, bronchodysplasia, or significant brain injury. A total of 146 children (63%) survived without any impairment. This is the first study to report neurodevelopmental outcomes at early school age in a Swiss cohort. The majority had favourable outcomes, but 21% of children demonstrated cognitive impairment, which was most pronounced in short-term memory. Our findings were similar to those of international cohorts and indicate that preterm children born before 300/7 gestational weeks, especially those living in unfavourable social environments, are at an increased risk of cognitive impairment and need close monitoring beyond early school age. Trial registration no: KEK-ZH-Nr.2014-0552 &nbsp.


Reliability, validity and diagnostic accuracy of palpation of the sciatic, tibial and common peroneal nerves in the examination of low back related leg pain.
This study investigated the reliability, validity and diagnostic accuracy of manual palpation of the sciatic, tibial and common peroneal nerves in the examination of 45 subjects with low-back related leg pain. The nerves were palpated manually and with an algometer, to determine pressure pain thresholds (PPTs). A second examiner performed the straight leg raise (SLR) and slump tests to determine nerve trunk mechanosensitivity. The procedure was repeated by another examiner to determine inter-rater reliability (n = 20). Kappa scores for agreement between raters for manual palpation were 0.80, 0.70 and 0.79 for the sciatic, tibial and common peroneal nerves respectively, demonstrating excellent reliability. PPTs were significantly lower on the symptomatic side, for each of the three nerves, in subjects who were positive on manual palpation. In subjects who were negative on manual palpation, PPTs were not significantly different between sides, demonstrating criterion-based validity, using PPT as the criterion. Highest scores of diagnostic accuracy were obtained when two or more of the three nerves were positive on palpation (sensitivity = 0.83; specificity = 0.73).


The relationships between nurses' perceptions of the hemodialysis unit work environment and nurse turnover, patient satisfaction, and hospitalizations.
While the nephrology nursing shortage persists despite the continued growth of the population of individuals with Stage 5 chronic kidney disease, there is a paucity of empirical data regarding nephrology nurses' perceptions of their work environments. Moreover, there are no studies that have examined the relationship of work environment attributes to patient and nurse outcomes in dialysis settings. The purpose of this study was to examine the relationships between staff nurses' perceptions of dialysis work environments, nurses' intentions to leave their current jobs, nurse turnover, patient satisfaction, and patient hospitalization rates. A descriptive, correlational design was used. Nurse level and facility level data were obtained. The sample for nurse-level data consisted of 199 registered nurses in staff nurse roles in 56 dialysis facilities of a national dialysis company. The sample for facility-level analysis consisted of 46 dialysis facilities, and nurse-level data were aggregated for facility-level analysis. The Practice Environment Scale-Nursing Work Index (PES-NWI) was used to measure nurses' perceptions of the dialysis work environment. Nurses' intention to leave their jobs and facility-level turnover rates were the nurse outcomes examined in this study. Facility-level patient satisfaction and hospitalization rates were the patient outcomes examined. Correlation coefficients were computed to measure the relationships between study variables, and independent t-tests were performed to examine subgroup differences in work environment perceptions. Overall, nurses rated the work environment somewhat favorably. Nurses who expressed intention to leave their jobs rated the work environment more negatively compared to nurses who intended to stay. Significant correlations were found between nurses' perceptions of the dialysis work environment, nurses' intention to leave their jobs, nurse turnover rates, and patient hospitalizations. Study findings suggest that nurses' perceptions of the dialysis work environment are important for nurse and patient outcomes in dialysis settings. Further research is needed to explore the predictive ability of the work environment for nurse and patient outcomes in hemodialysis units.


Macroscopic and microscopic details of the cartilaginous nasal pyramid.
The purpose of this investigation was to ascertain the macroscopic and microscopic details at rhinion and throughout the cartilaginous nasal pyramid in 35 white cadavers. Demographic information on 35 white cadavers was collected. This included sex, height, weight, brief medical history, age at death, and cause of death. All soft tissues were removed from the nasal bones, lateral nasal cartilages, and alar cartilages and the overlap between bone and cartilage was measured at 4 sites. The lateral nasal cartilage (LNC) was measured for width and length. The relationship between the caudal end of the LNC, and the anterior septal angle was also noted. The septum and LNC were removed en bloc randomly from 25 of the cadavers. These specimens were fixed in formalin, processed, embedded in paraffin, and coronally sectioned every 3 mm, and prepared for microscopic examination. The LNC was 22.51 mm long and 13.71 mm wide on average. It underlapped the nasal bone 14.97 mm on average from the nasal septum laterally. The cephalocaudal underlapping was greatest in the midline (mean, 8.63 mm) and least (2.77 mm) about halfway down the nasal bone. Microscopic examination showed extreme variation in the attachment of the septum and LNC. This ranged from no cartilaginous connection to complete fusion. Thirty-two percent of the specimens showed the caudal edge of the LNC to be coincident with the anterior septal angle. At the time of aesthetic, functional, or post-traumatic nasal surgery, one must be prepared to deal with diverse attachments between the septum and the LNC.


An integrated analysis of acute treatment-emergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine.
The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (- 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database. This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared. A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p <.001) or risperidone-treated patients (p =.047). A significantly greater percentage of haloperidol-treated patients experienced parkinsonian (p <.001) and akathisia (p <.001) events than did olanzapine-treated patients. Categorical analysis of Simpson-Angus Scale scores showed significantly more haloperidol- (p <.001) or risperidone-treated patients (p =.004) developed parkinsonism than did olanzapine-treated patients. Olanzapine-treated patients experienced significantly greater reductions in Simpson-Angus Scale scores than did haloperidol- (p <.001), risperidone- (p <.001), or clozapine-treated (p =.032) patients. Categorical analysis of BAS scores showed significantly more haloperidol-treated patients experienced treatment-emergent akathisia versus olanzapine-treated patients (p <.001). Significantly greater reductions in BAS scores were experienced during olanzapine treatment versus placebo (p =.007), haloperidol (p <.001), and risperidone (p =.004) treatments. A significantly smaller percentage of olanzapine-treated patients received anticholinergic medications compared with that of haloperidol- (p <.001) or risperidone-treated patients (p =.018). Compared with that in olanzapine-treated patients, the duration of anticholinergic cotreatment was significantly longer among haloperidol- (p <.001) or risperidone-treated patients (p =.040) and significantly shorter among clozapine-treated patients (p =.021). This analysis of available data from olanzapine clinical trials lends additional support to olanzapine's favorable EPS profile.


Foundations for Studying Clinical Workflow: Development of a Composite Inter-Observer Reliability Assessment for Workflow Time Studies.
The ability to understand and measure the complexity of clinical workflow provides hospital managers and researchers with the necessary knowledge to assess some of the most critical issues in healthcare. Given the protagonist role of workflow time studies on influencing decision makers, major efforts are being conducted to address existing methodological inconsistencies of the technique. Among major concerns, the lack of a standardized methodology to ensure the reliability of human observers stands as a priority. In this paper, we highlight the limitations of the current Inter-Observer Reliability Assessments, and propose a novel composite score to systematically conduct them. The composite score is composed of a) the overall agreement based on Kappa that evaluates the naming agreement on virtually created one-seconds tasks, providing a global assessment of the agreement over time, b) a naming agreement based on Kappa, requiring an observation pairing approach based on time-overlap, c) a duration agreement based on the concordance correlation coefficient, that provides means to evaluate the correlation concerning tasks duration, d) a timing agreement, based on descriptive statistics of the gaps between timestamps of same-task classes, and e) a sequence agreement based on the Needleman-Wunsch sequence alignment algorithm. We hereby provide a first step towards standardized reliability reporting in workflow time studies. This new composite IORA protocol is intended to empower workflow researchers with a standardized and comprehensive method for validating observers' reliability and, in turn, the validity of their data and results.


USP14-regulated allostery of the human proteasome by time-resolved cryo-EM.
Proteasomal degradation of ubiquitylated proteins is tightly regulated at multiple levels1-3. A primary regulatory checkpoint is the removal of ubiquitin chains from substrates by the deubiquitylating enzyme ubiquitin-specific protease 14 (USP14), which reversibly binds the proteasome and confers the ability to edit and reject substrates. How USP14 is activated and regulates proteasome function remain unknown4-7. Here we present high-resolution cryo-electron microscopy structures of human USP14 in complex with the 26S proteasome in 13 distinct conformational states captured during degradation of polyubiquitylated proteins. Time-resolved cryo-electron microscopy analysis of the conformational continuum revealed two parallel pathways of proteasome state transitions induced by USP14, and captured transient conversion of substrate-engaged intermediates into substrate-inhibited intermediates. On the substrate-engaged pathway, ubiquitin-dependent activation of USP14 allosterically reprograms the conformational landscape of the AAA-ATPase motor and stimulates opening of the core particle gate8-10, enabling observation of a near-complete cycle of asymmetric ATP hydrolysis around the ATPase ring during processive substrate unfolding. Dynamic USP14-ATPase interactions decouple the ATPase activity from RPN11-catalysed deubiquitylation11-13 and kinetically introduce three regulatory checkpoints on the proteasome, at the steps of ubiquitin recognition, substrate translocation initiation and ubiquitin chain recycling. These findings provide insights into the complete functional cycle of the USP14-regulated proteasome and establish mechanistic foundations for the discovery of USP14-targeted therapies.


[The osteomyoplastic flap, a contribution to neurosurgery].
the cosmetic deformities that appear after a pterional craniotomy are usually the result of atrophy of the temporal muscle, lesion of the frontotemporal branch of the facial nerve or occur as a consequence of the way the craniotomy was done.The objective was to compare the functional and aesthetic complications from both the classic pterional approach and the osteomyoplastic flap type approach in patients with supratentorial surgical pathology either vascular or tumoral. a retrospective observational comparative survey was done. All the patients operated on who required a pterional approach for a supratentorial pathology and were given either a classic pterional approach or an osteomyoplastic pterional flap were included. the variables: surgical time and hollowing had significant differences; the pterional approach with less operative time (p < 0.001) and the osteomyoplastic approach with less hollowing perceived by the patients (p = 0.013). the osteomyoplastic flap showed a less severe hollowing in the temple although it demands more time in order to perform it. The frequency of complications seems to be the same.


A metalloproteomic analysis of interactions between plasma proteins and zinc: elevated fatty acid levels affect zinc distribution.
Serum albumin is a highly abundant plasma protein associated with the transport of metal ions, pharmaceuticals, fatty acids and a variety of small molecules in the blood. Once thought of as a molecular 'sponge', mounting evidence suggests that the albumin-facilitated transport of chemically diverse entities is not independent. One such example is the transport of Zn2+ ions and non-esterified 'free' fatty acids (FFAs) by albumin, both of which bind at high affinity sites located in close proximity. Our previous research suggests that their transport in blood plasma is linked via an allosteric mechanism on serum albumin. In direct competition, albumin-bound FFAs significantly decrease the binding capacity of albumin for Zn2+, with one of the predicted consequences being a change in plasma/serum zinc speciation. Using liquid chromatography (LC), ICP-MS and fluorescence assays, our work provides a quantitative assessment of this phenomenon, and finds that in the presence of high FFA concentrations encountered in various physiological conditions, a significant proportion of albumin-bound Zn2+ is re-distributed amongst plasma/serum proteins. Using peptide mass fingerprinting and immunodetection, we identify candidate acceptor proteins for Zn2+ liberated from albumin. These include histidine-rich glycoprotein (HRG), a multifunctional protein associated with the regulation of blood coagulation, and members of the complement system involved in the innate immune response. Our findings highlight how FFA-mediated changes in extracellular metal speciation might contribute to the progression of certain pathological conditions.


Commercially Available Ion-Releasing Dental Materials and Cavitated Carious Lesions: Clinical Treatment Options.
The contemporary approach for operative caries management emphasizes personalized interventions for each patient, dependent upon the individual's caries susceptibility/risk, the stage of the carious lesion and its activity. The clinician's challenge is to optimize the extent of cavity preparation and the choice of dental restorative biomaterials, appreciating the benefits offered by ion-releasing restorative materials. There is a growing application of bioactive/bio-interactive materials in minimally invasive operative dentistry, as they may help with tissue recovery by ion release. In case of moderate or extensive occlusal cavitation, the clinical criteria include the individual caries susceptibility and carious lesion activity. In high caries risk cases, ion-releasing biomaterials (IRB) can be used, as well as for active carious lesions. In proximal lesions, the clinical criteria include the individual caries susceptibility, the lesion activity and presence of cavities with little or no enamel at the gingival margin. This article aims to discuss the restorative ion-releasing options, according to different clinical situations, and the caries susceptibility to manage cavitated carious lesions in permanent adult teeth.


Human bony labyrinth is an indicator of population history and dispersal from Africa.
The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype-phenotype comparisons.


Relationship between ATM and ribosomal protein S6 revealed by the chemical inhibition of Ser/Thr protein phosphatase type 1.
The optimal cellular responses to DNA damage are modulated by kinase and phosphatase. The ataxia telangiectasia mutated (ATM) is a Ser/Thr kinase which is the core of the DNA damage signaling apparatus. The Ser/Thr protein phosphatase type 1 (PP1) inhibitor, tautomycetin (TC) and an antibody to the phospho-(S/T)Q sites of the ATM substrate were used to identify the common substrates for PP1 and ATM in regulating the pathway for DNA damage response. Ribosomal protein S6 (RPS6) was first identified as a substrate for PP1 and ATM. The phosphorylation at Ser247 of RPS6 was then significantly decreased by PP1-mediated dephosphorylation immediately after UV irradiation. These results suggest that PP1 specifically dephosphorylated RPS6 at phospho-Ser247 in vivo. In response to DNA damage, ATM activity was finally required for the phosphorylation of RPS6 at Ser247. We propose from these results a novel mechanism for modulating the RPS6 function by PP1 and ATM which regulates cell growth and survival in response to DNA-damage stimuli.


Ontogenesis of the asymmetric parapineal organ in the zebrafish epithalamus.
The parapineal organ is a midline-derived epithalamic structure that in zebrafish adopts a left-sided position at embryonic stages to promote the development of left-right asymmetries in the habenular nuclei. Despite extensive knowledge about its embryonic and larval development, it is still unknown whether the parapineal organ and its profuse larval connectivity with the left habenula are present in the adult brain or whether, as assumed from historical conceptions, this organ degenerates during ontogeny. This paper addresses this question by performing an ontogenetic analysis using an integrative morphological, ultrastructural and neurochemical approach. We find that the parapineal organ is lost as a morphological entity during ontogeny, while parapineal cells are incorporated into the posterior wall of the adult left dorsal habenular nucleus as small clusters or as single cells. Despite this integration, parapineal cells retain their structural, neurochemical and connective features, establishing a reciprocal synaptic connection with the more dorsal habenular neuropil. Furthermore, we describe the ultrastructure of parapineal cells using transmission electron microscopy and report immunoreactivity in parapineal cells with antibodies against substance P, tachykinin, serotonin and the photoreceptor markers arrestin3a and rod opsin. Our findings suggest that parapineal cells form an integral part of a neural circuit associated with the left habenula, possibly acting as local modulators of the circuit. We argue that the incorporation of parapineal cells into the habenula may be part of an evolutionarily relevant developmental mechanism underlying the presence/absence of the parapineal organ in teleosts, and perhaps in a broader sense in vertebrates.


Intercountry Differences in Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure.
The aim of this study was to examine patterns of care and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) in the United States and Canada. In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial, the use of N-terminal pro-B-type natriuretic peptide-guided titration of guideline-directed medical therapy (GDMT) was compared with usual care alone for patients with HFrEF in the United States and Canada. It remains unknown whether the country of enrollment had an impact on outcomes or GDMT use. A total of 894 patients at 45 sites across the United States and Canada with HFrEF (ejection fraction ≤40%) were enrolled in the trial. Kaplan-Meier survival estimates stratified by country of enrollment were developed for the trial outcomes, and log-rank testing was compared between the groups. GDMT use and titration were also compared. U.S. patients were more likely to be younger, to be Black, to have higher body mass index, and to have histories of defibrillator placement or sleep apnea. Use of β-blockers was significantly higher in Canada at baseline (99.3% vs. 94.0%; p = 0.01) and 6 months (99.0% vs. 94.1%; p = 0.04), and use of mineralocorticoid receptor antagonists was higher in Canada at 6 months (68.3% vs. 55.1%; p = 0.01). Canadian patients were less likely to experience the primary study endpoint (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.45 to 0.93; p = 0.01) due to decreased rates of HF hospitalization (HR: 0.57; 95% CI: 0.38 to 0.86; p = 0.003). The differences in outcomes were driven by increased heart failure hospitalization among U.S. Black patients. In GUIDE-IT, patients with HFrEF in Canada were significantly less likely to be hospitalized for heart failure. Differences in GDMT use, along with differences in sociodemographics and care delivery structures, may contribute to these differences, highlighting the importance of increasing diversity in clinical trials. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).


Hair transplant surgery: planning the procedure.
Factors important in planning hair transplant surgery are presented. The procedure must be designed for each patient individually. Success with hair transplantation depends upon developing surgical skill and having an appreciation of esthetically pleasing designs.


Medically assisted hydration for adult palliative care patients.
Many palliative care patients have reduced oral intake during their illness. The management of this can include the provision of medically assisted hydration with the aim of prolonging the life of a patient, improving their quality of life, or both. This is an updated version of the original Cochrane review published in Issue 2, 2008, and updated in February 2011. To determine the effect of medically assisted hydration in palliative care patients on their quality and length of life. We identified studies by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, CANCERLIT, Caresearch, Dissertation abstracts, SCIENCE CITATION INDEX and the reference lists of all eligible studies, key textbooks and previous systematic reviews. The date of the latest search conducted on CENTRAL, MEDLINE and EMBASE was March 2014. All relevant randomised controlled trials (RCTs) or prospective controlled studies of medically assisted hydration in palliative care patients. We identified six relevant studies for this update. These included three RCTs (222 participants), and three prospective controlled trials (360 participants). Two review authors independently assessed the studies for quality and validity. The small number of studies and the heterogeneity of the data meant that a quantitative analysis was not possible, so we included a description of the main findings. One study found that sedation and myoclonus (involuntary contractions of muscles) scores were improved more in the intervention group. Another study found that dehydration was significantly higher in the non-hydration group, but that some fluid retention symptoms (pleural effusion, peripheral oedema and ascites) were significantly higher in the hydration group. The other four studies (including the three RCTs) did not show significant differences in outcomes between the two groups. The only study that had survival as an outcome found no difference in survival between the hydration and control arms. Since the last version of this review, we found one new study. The studies published do not show a significant benefit in the use of medically assisted hydration in palliative care patients; however, there are insufficient good-quality studies to inform definitive recommendations for practice with regard to the use of medically assisted hydration in palliative care patients.


The Impact of Sarcopenia in Patients with Peritoneal Surface Disease.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is increasingly performed in patients with advanced cancer in the abdomen. This treatment prolongs survival for some patients but is known to have a substantial rate of complications. Choosing patients for this procedure can be difficult, and no clear guidelines exist. Muscle mass is a general measure of a patient's wellness, meaning that patients with low muscle mass for their body weight tend to have more complications from treatment and overall do worse. We evaluated muscle mass prior to surgery in our Cytoreductive surgery/hyperthermic intraperitoneal chemotherapy population to assess how many patients have low muscle mass and the impact on outcomes, such as length of hospital stay, complications and survival. We find that about 25% of our patient population has low muscle mass, and low muscle mass is associated with a higher burden of cancer and shorter survival. We were able to evaluate muscle mass in a small number of patients after surgery, expecting to find decreased muscle mass in all the patients after a complex operation and long recovery. In fact, none of the patients had low muscle mass, including those who were low prior to surgery.


Structural properties of ZnO nanotubes under uniaxial strain: molecular dynamics simulations.
Structural properties of zinc oxide nanotubes with zigzag, armchair and chiral geometries have been investigated by performing classical molecular dynamics simulations. An atomistic potential energy function has been used to represent the interactions among the atoms. Strain has been applied to the generated ZnO nanostructures along their length, which has been realized at two different temperatures, 1 K and 300 K. It has been found that ZnO nanostructures following strain application undergo a structural change depending on temperature, geometry and tube radius.


Antisocial behavior in the transition to adulthood: the independent and interactive roles of developmental history and emerging developmental tasks.
Although the turning points theory posits that the successful engagement of the romantic and work domains in young adulthood represents an important opportunity for disrupting antisocial pathways, others have recently speculated that such turning points may be most applicable to the majority of antisocial youth who begin offending in adolescence (Adolescence-Onset [AO]), rather than those who begin early in childhood and persist (Early-Onset/Persistent [EOP]). This study was designed (a) to attempt replication of recent evidence that AOs demonstrate problem behaviors intermediate to EOP and Never Antisocial youth in young adulthood, which was confirmed; and (b) to examine the correlates of lower levels of antisocial offending among AOs and EOPs in the transition to adulthood. As expected, AOs were more likely than EOPs to desist by age 23. Nonetheless, positive work and romantic involvement between the ages of 21 and 23 were significantly associated with less externalizing problems for EOPs, but not AOs. In addition, illicit substance use and deviant peer association proved to be associated with externalizing problems at age 23, irrespective of the patterning of young adults' antisocial behavior in childhood and adolescence. Results suggest that the unique opportunities available in the transition to adulthood may hold particular promise for youth with persistently troubled early histories.


The HIV-1 Antisense Protein ASP Is a Transmembrane Protein of the Cell Surface and an Integral Protein of the Viral Envelope.
The negative strand of HIV-1 encodes a highly hydrophobic antisense protein (ASP) with no known homologs. The presence of humoral and cellular immune responses to ASP in HIV-1 patients indicates that ASP is expressed in vivo, but its role in HIV-1 replication remains unknown. We investigated ASP expression in multiple chronically infected myeloid and lymphoid cell lines using an anti-ASP monoclonal antibody (324.6) in combination with flow cytometry and microscopy approaches. At baseline and in the absence of stimuli, ASP shows polarized subnuclear distribution, preferentially in areas with low content of suppressive epigenetic marks. However, following treatment with phorbol 12-myristate 13-acetate (PMA), ASP translocates to the cytoplasm and is detectable on the cell surface, even in the absence of membrane permeabilization, indicating that 324.6 recognizes an ASP epitope that is exposed extracellularly. Further, surface staining with 324.6 and anti-gp120 antibodies showed that ASP and gp120 colocalize, suggesting that ASP might become incorporated in the membranes of budding virions. Indeed, fluorescence correlation spectroscopy studies showed binding of 324.6 to cell-free HIV-1 particles. Moreover, 324.6 was able to capture and retain HIV-1 virions with efficiency similar to that of the anti-gp120 antibody VRC01. Our studies indicate that ASP is an integral protein of the plasma membranes of chronically infected cells stimulated with PMA, and upon viral budding, ASP becomes a structural protein of the HIV-1 envelope. These results may provide leads to investigate the possible role of ASP in the virus replication cycle and suggest that ASP may represent a new therapeutic or vaccine target.IMPORTANCE The HIV-1 genome contains a gene expressed in the opposite, or antisense, direction to all other genes. The protein product of this antisense gene, called ASP, is poorly characterized, and its role in viral replication remains unknown. We provide evidence that the antisense protein, ASP, of HIV-1 is found within the cell nucleus in unstimulated cells. In addition, we show that after PMA treatment, ASP exits the nucleus and localizes on the cell membrane. Moreover, we demonstrate that ASP is present on the surfaces of viral particles. Altogether, our studies identify ASP as a new structural component of HIV-1 and show that ASP is an accessory protein that promotes viral replication. The presence of ASP on the surfaces of both infected cells and viral particles might be exploited therapeutically.


Understanding and predicting druggability. A high-throughput method for detection of drug binding sites.
Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform ( http://fpocket.sourceforge.net/dcd ) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremely fast, and can effectively be used to automatically sieve through massive collections of structures ( http://fpocket.sourceforge.net ).


Mutation update for the SATB2 gene.
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.


Enhancing fire department home visiting programs: results of a community intervention trial.
This study evaluates the impact of an enhanced fire department home visiting program on community participation and installation of smoke alarms, and describes the rate of fire and burn hazards observed in homes. Communities were randomly assigned to receive either a standard or enhanced home visiting program. Before implementing the program, 603 household surveys were completed to determine comparability between the communities. During a 1-year intervention period, 171 home visits took place with 8080 homes. At baseline, 60% of homes did not have working smoke alarms on every level, 44% had unsafe water temperatures, and 72% did not have carbon monoxide alarms. Residents in the enhanced community relative to those in the standard community were significantly more likely to let the fire fighters into their homes (75 vs 62%). Among entered homes, those in the enhanced community were significantly more likely to agree to have smoke alarms installed (95 vs 92%), to be left with a working smoke alarm on every level of the home (84 vs 78%), and to have more smoke alarms installed per home visited (1.89 vs 1.74). The high baseline rates of home hazards suggest that fire department home visiting programs should take an "all hazards" approach. Community health workers and community partnerships can be effective in promoting fire departments' fire and life safety goals. Public health academic centers should partner with the fire service to help generate evidence on program effectiveness that can inform decision making about resource allocation for prevention.


Update of the ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage (ULTRA) trial: statistical analysis plan.
Recurrent bleeding from an intracranial aneurysm after subarachnoid hemorrhage (SAH) is associated with unfavorable outcome. Recurrent bleeding before aneurysm occlusion can be performed occurs in up to one in five patients and most often happens within the first 6 h after the primary hemorrhage. Reducing the rate of recurrent bleeding could be a major factor in improving clinical outcome after SAH. Tranexamic acid (TXA) reduces the risk of recurrent bleeding but has thus far not been shown to improve functional outcome, probably because of a higher risk of delayed cerebral ischemia (DCI). To reduce the risk of ultraearly recurrent bleeding, TXA should be administered as soon as possible after diagnosis and before transportation to a tertiary care center. If TXA is administered for a short duration (i.e., < 24 h), it may not increase the risk of DCI. The aim of this paper is to present in detail the statistical analysis plan (SAP) of the ULTRA trial (ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage), which is currently enrolling patients and investigating whether ultraearly and short-term TXA treatment in patients with aneurysmal SAH improves clinical outcome at 6 months. The ULTRA trial is a multicenter, prospective, randomized, open, blinded endpoint, parallel-group trial currently ongoing at 8 tertiary care centers and 16 of their referral centers in the Netherlands. Participants are randomized to standard care or to receive TXA at a loading dose of 1 g, immediately followed by 1 g every 8 h for a maximum of 24 h, in addition to standard care, as soon as SAH is diagnosed. In the TXA group, TXA administration is stopped immediately prior to treatment (coil or clip) of the causative aneurysm. Primary outcome is the modified Rankin Scale (mRS) score at 6 months after SAH, dichotomized into good (mRS 0-3) and poor (mRS 4-6) outcomes, assessed blind to treatment allocation. Secondary outcomes include case fatalities at 30 days and at 6 months and causes of poor clinical outcome. Safety outcomes are recurrent bleeding, DCI, hydrocephalus, per-procedural complications, and other complications such as infections occurring during hospitalization. Data analyses will be according to this prespecified SAP. Netherlands Trial Register, NTR3272. Registered on 25 January 2012. ClinicalTrials.gov, NCT02684812. Registered on 17 February 2016.


KNOTS IN LEUCOTHRIX MUCOR.
The filaments of Leucothrix mucor are able to form true knots under certain cultural conditions. Such structures have apparently not been previously seen in filamentous organisms. As the culture ages, the knots become tighter and eventually the cells in the knot region fuse and form a large bulb. The filament breaks on each side of the bulb, and two shorter filaments anda free bulb are produced. The free bulbs have not been observed to grow into new filaments.


Cerebral Temperature Dysregulation: MR Thermographic Monitoring in a Nonhuman Primate Study of Acute Ischemic Stroke.
Cerebral thermoregulation remains poorly understood. Temperature dysregulation is deeply implicated in the potentiation of cerebrovascular ischemia. We present a multiphasic, MR thermographic study in a nonhuman primate model of MCA infarction, hypothesizing detectable brain temperature disturbances and brain-systemic temperature decoupling. Three Rhesus Macaque nonhuman primates were sourced for 3-phase MR imaging: 1) baseline MR imaging, 2) 7-hour continuous MR imaging following minimally invasive, endovascular MCA stroke induction, and 3) poststroke day 1 MR imaging follow-up. MR thermometry was achieved by multivoxel spectroscopy (semi-localization by adiabatic selective refocusing) by using the proton resonance frequency chemical shift. The relationship of brain and systemic temperatures with time and infarction volumes was characterized by using a mixed-effects model. Following MCA infarction, progressive cerebral hyperthermia was observed in all 3 subjects, significantly outpacing systemic temperature fluctuations. Highly significant associations were observed for systemic, hemispheric, and global brain temperatures (F-statistic, P = .0005 for all regressions) relative to the time from stroke induction. Significant differences in the relationship between temperature and time following stroke onset were detected when comparing systemic temperatures with ipsilateral (P = .007), contralateral (P = .004), and infarction core (P = .003) temperatures following multiple-comparisons correction. Significant associations were observed between infarction volumes and both systemic (P ≤ .01) and ipsilateral (P = .04) brain temperatures, but not contralateral brain temperature (P = .08). Successful physiologic and continuous postischemic cerebral MR thermography was conducted and prescribed in a nonhuman primate infarction model to facilitate translatability. The results confirm hypothesized temperature disturbance and decoupling of physiologic brain-systemic temperature gradients. These findings inform a developing paradigm of brain thermoregulation and the applicability of brain temperature as a neuroimaging biomarker in CNS injury.


[Nature of the regulation of blood circulation in pilots].
Dynamic observations over a group of pilots within a working week during three months have shown that blood pressure increases to meet the requirements via a higher cardiac output. When stresses grow and fatigue sets in, the pattern of circulation regulation changes so that elevated blood pressure is maintained due to an increased peripheral resistance. Differential approach to the pattern of blood pressure regulation makes it possible to assess the degree of circulation adaptation to various work loads.


The Results of Two-stage Revision for Methicillin-resistant Periprosthetic Joint Infection (PJI) of the Hip.
Periprosthetic joint infection (PJI) of the hip due to methicillin-resistant bacteria is difficult to treat and remain a challenge for arthroplasty surgeon. Retrospective review was done to the patients who received two-stage revisions with an antibiotic loaded cement-spacer for PJI of the hip between January 2010 to May 2015. We found 65 patients (65 hips) with positive culture findings. Eight patients were lost to follow-up and excluded from the study. Among the rest of the 57 patients, methicillin-resistant infection (MR Group) was found in 28 cases. We also evaluate the 29 other cases that caused by the other pathogen as control group. We compared all of the relevant medical records and the treatment outcomes between the two groups. The mean of follow-up period was 33.7 months in the methicillin-resistant group and 28.4 months in the control group (p = 0.27). The causal pathogens in the methicillin-resistant group were: Methicillin-resistant Staphylococcus aureus (MRSA) in 10 cases, Methicillin-resistant Staphylococcus epidermidis (MRSE) in 16 cases and Methicillin-resistant coagulase-negative Staphylococcus (MRCNS) in two cases. The reimplantation rate was 92.8% and 89.6% in the methicillin-resistant and control group, respectively (p= 0.66). The rates of recurrent infection after reimplantation were 23.1% (6/26) in the methicillin-resistant group and 7.6% (2/26) in the control group (p= 0.12). The overall infection control rate was 71.4% (20/28) and 89.6% (26/29) in the methicillin-resistant and control group, respectively (p = 0.08). Both groups showed comparable baseline data on mean age, BMI, gender distribution, preoperative ESR/CRP/WBC and comorbidities. Two-stage revision procedure resulted in low infection control rate and high infection recurrency rate for the treatment of methicillin-resistant periprosthetic joint infection (PJI) of the hip. Development of the treatment strategy is needed to improve the outcome of methicillin-resistant periprosthetic joint infection (PJI) of the hip.


Myeloablative conditioning regimens for AML allografts: 30 years later.
During the last three decades, several myeloablative conditioning regimens have been used for AML allografts. In this review, we systematically examine the data from studies reporting on myeloablative conditioning regimens for AML allografts. High-dose busulfan combined with cyclophosphamide (BuCy) and cyclophosphamide in combination with total body irradiation (CyTBI) are the two most commonly used conditioning regimens for AML allografts. From the available data, there are no significant differences in survival with these two regimens. A small benefit of decreased relapse rate with CyTBI is counterbalanced by a nonsignificant increase in treatment-related mortality. The incidence of veno-occlusive disease is significantly higher in patients treated with BuCy. Therapeutic monitoring of busulfan was not reported in any of the studies comparing the regimens. Either of the regimens can be used for AML allografts, and the choice may ultimately depend on local availability and expertise. Further improvements may be possible from modifications of the standard regimens. Data from these latter studies seem to be encouraging, but are not based on comparative randomized trials.


Burkitt's lymphoma with bilateral cavernous sinus and mediastinal involvement in a child.
We report a 12-year-old boy who presented with incomplete right ophthalmoplegia, exophthalmos and headache. Initial CT and MRI revealed a mass in the right cavernous sinus. During tumour work-up, CT identified additional tumour within the mediastinum. Biopsy of the mediastinal lesion identified Burkitt's lymphoma. We report on this case because radiologists and clinicians should be alerted to identify sites of primary Burkitt's lymphoma outside of the central nervous system if clinical symptoms indicate, or imaging shows, CNS lesions. Primary CNS involvement in Burkitt's lymphoma is rare.


Risk factors for and incidence of hospital-acquired infections after cardiac surgery in children with congenital heart disease: a single center experience.
The epidemiology of hospital-acquired infections (HAIs) has been less well studied in critically ill children in pediatric cardiothoracic intensive care units. This study aimed to investigate independent risk factors for and incidence of HAIs after cardiac surgery in children with congenital heart disease (CHD). Our study included 574 patients who underwent congenital heart surgery and were followed up in the cardiothoracic intensive care unit between September 2016 and December 2020. All patients were divided into four groups according to age: 0-1 months, 1-6 months, 6-12 months, and 1-18 years, and into two subgroups according to HAI development. The patients` median age and weight at surgery were 3.28 (interquartile range [IQR]): 0.43-8.1) months and 4.34 (IQR: 4.34-6.69) kg, respectively. HAIs and infection-related deaths were observed in 223 and 21 patients, respectively. Age at surgery, weight at surgery, concomitant syndromes and immunodeficiency status, presence of cyanotic heart disease, intubation, and use of antibiotics during hospitalization were statistically significant between the two groups with and without infection (p < 0.05). In logistic regression analysis, surgical weight < 5 kg (odds ratio [OR]: 2.55; 95% confidence interval [CI]: 1.56-4.17; p < 0.001), preoperative mechanical ventilation (OR: 2.0; 95% CI: 1.26-3.12; p=0.003), complexity of cardiac surgery according to the risk-adjusted congenital heart surgery classification score 3 (OR: 3.13; 95% CI: 1.24-7.92; p=0.016), presence of an concomitant syndrome (OR: 1.56; 95% CI: 1.02-2.88; p=0.040), age (OR: 1.01; 95% CI: 1.01-1.04; p=0.044) were independent risk factors for HAIs after cardiac surgery in children with CHD. In this study, younger age, presence of an associated syndrome, preoperative mechanical ventilation, and weight less than 5 kg were found to be independent risk factors for HAI after cardiac surgery in children with CHD.


Short-Term Retinal Sensitivity and Metamorphopsia Changes following Half-Fluence Photodynamic Therapy in Central Serous Chorioretinopathy.
The aim of this study was to investigate the short-term retinal sensitivity and metamorphopsia changes after half-fluence photodynamic therapy (PDT) in patients with central serous chorioretinopathy (CSC). Patients with acute CSC and evidence of angiographic leakage and subretinal fluid on optical coherence tomography (OCT) were enrolled. Before, and 1 week (W-1) and 2 months (M-2) after PDT, all patients underwent best-corrected visual acuity, enhanced depth imaging OCT, microperimetry (MP) and preferential hyperacuity perimetry (PHP). We considered 'affected' the Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors showing a mean retinal thickness greater than 350 μm on the baseline OCT thickness map. MP retinal sensitivity, PHP 'score' and retinal thickness were measured in each ETDRS 'affected sector'. Functional correlation between MP and PHP was also investigated. Twelve eyes of 12 patients were included. MP and PHP correlated with each other at baseline (p = 0.04) but not at W-1 (p = 0.12) and M-2 (p = 0.05). Mean MP retinal sensitivity slightly improved from 12.9 ± 5.0 dB at baseline to 14.5 ± 4.7 dB at M-2 (p = 0.2). The PHP score changed from 0.33 at baseline to 0.32 at M-2 (p = 0.3). In the ETDRS 'affected sectors', MP retinal sensitivity improved significantly from 12.9 ± 5.0 dB at baseline to 14.5 ± 4.7 dB at M-2 (p = 0.03), whereas the PHP score did not show significant changes over time. Half-fluence PDT achieved short-term improvement in the sensitivity of the retinal 'affected sectors' but did not influence metamorphopsia as measured on PHP in patients with acute CSC.


Functional evaluation of the insulin/insulin-like growth factor signaling pathway in determination of wing polyphenism in pea aphid.
Wing polyphenism is a common phenomenon that plays key roles in environmental adaptation of insects. Insulin/insulin-like growth factor signaling (IIS) pathway is a highly conserved pathway in regulation of metabolism, development, and growth in metazoans. It has been reported that IIS is required for switching of wing morph in brown planthopper via regulating the development of the wing pad. However, it remains elusive whether and how IIS pathway regulates transgenerational wing dimorphism in aphid. In this study, we found that pairing and solitary treatments can induce pea aphids to produce high and low percentage winged offspring, respectively. The expression level of ILP5 (insulin-like peptide 5) in maternal head was significantly higher upon solitary treatment in comparison with pairing, while silencing of ILP5 caused no obvious change in the winged offspring ratio. RNA interference-mediated knockdown of FoxO (Forkhead transcription factor subgroup O) in stage 20 embryos significantly increased the winged offspring ratio. The results of pharmacological and quantitative polymerase chain reaction experiments showed that the embryonic insulin receptors may not be involved in wing polyphenism. Additionally, ILP4 and ILP11 exhibited higher expression levels in 1st wingless offspring than in winged offspring. We demonstrate that FoxO negatively regulates the wing morph development in embryos. ILPs may regulate aphid wing polyphenism in a developmental stage-specific manner. However, the regulation may be not mediated by the canonical IIS pathway. The findings advance our understanding of IIS pathway in insect transgenerational wing polyphenism.


Human biomonitoring of deoxynivalenol (DON) - Assessment of the exposure of young German adults from 1996 - 2021.
The mycotoxin deoxynivalenol (DON) is a frequently found contaminant in cereals and cereal-based products. As a German contribution to the European Joint Programme HBM4EU, we analysed the total DON concentration (tDON) in 24-h urine samples from the German Environmental Specimen Bank (ESB). In total, 360 samples collected in 1996, 2001, 2006, 2011, 2016, and 2021 from young adults in Muenster (Germany), were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) after enzymatic deconjugation of the glucuronide metabolites. tDON was found in concentrations above the lower limit of quantification (0.3 μg/L) in 99% of the samples. Medians of the measured concentrations and the daily excretion were 4.3 μg/L and 7.9 μg/24 h, respectively. For only nine participants, urinary tDON concentrations exceeded the provisional Human biomonitoring guidance value (HBM GV) of 23 μg/L. Urinary tDON concentrations were significantly higher for male participants. However, 24-h excretion values normalized to the participant's body weight did not exhibit any significant difference between males and females and the magnitude remained unchanged over the sampling years with exception of the sampling year 2001. Daily intakes were estimated from excretion values. Exceedance of the tolerable daily intake (TDI) of 1 μg/kg bw per day was observed for less than 1% of all participants. TDI exceedances were only present in the sampling year 2001 and not in more recent sampling years while exceedance of the HBM guidance value was also observed in 2011 and 2021.


[Outbreak of 18 cases of hepatitis C in a hemodialysis unit].
On September 30, 2001 we had notice of a probable outbreak of hepatitis C virus (HCV) infection in a hemodialysis unit in Ciudad Real (Spain). We conducted an investigation of the outbreak to determine its cause and implement control measures. We performed a descriptive study and another analytic study (retrospective cohort study). In the descriptive study, the incidence of HCV infection in the unit between 01/01/98 and 09/30/01 was studied. In the cohort study, 86 subjects were included, of which 18 were infected with HCV during the outbreak. Virologic study was performed, including serology of anti-HCV antibodies, specific IgG avidity study, polymerase chain reaction and phylogenetic analysis of the viral subtypes found. In the study period, there were 86 patients under treatment in the hemodialysis unit, of which 27 (31.4%) were HCV-positive before 03/01/01. The epidemic curve suggested a common source with secondary cases. Since 1998 only one seroconversion had been documented (in 1999). Statistically significant differences were found only for the variable of dialysis shift. None of the patients who underwent dialysis on the Tuesday-Saturday-Thursday shift exclusively was infected. All cases were genosubtype 4d, which is uncommon in Spain (accounting for 3%), suggesting a common initial source for all cases. Most of the previous cases of HCV in the hemodialysis unit were 1b; three were 4c/4d and one was 1a. The IgG avidity study suggested that not all the cases were infected at the same time, supporting the hypothesis of a common source with secondary spread. The outbreak of HCV was confirmed, with 18 cases among dialyzed patients in the central unit. The outbreak was caused by the same viral strain, probably due to a common source with secondary person-to-person transmission among the patients.


Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity.
TNF-related apoptosis-inducing ligand (TRAIL) has been identified as a member of the TNF family that induces apoptosis in a variety of tumor cells, but its physiological functions are largely unknown. In the present study, we examined the expression and function of TRAIL in human CD4+ T cell clones by utilizing newly established anti-human TRAIL mAbs. Human CD4+ T cell clones, HK12 and 4HM1, exhibited perforin-independent and Fas ligand (FasL)-independent cytotoxicity against certain target cells, including T lymphoma (Jurkat) and keratinocyte (HaCaT) cell lines, which are susceptible to TRAIL-mediated cytotoxicity. In contrast to FasL, the expression of which was inducible upon anti-CD3 stimulation, TRAIL was constitutively expressed on HK12 and 4HM1 cells, and no further increase was observed after anti-CD3 stimulation. Spontaneous cytotoxic activities of resting HK12 and 4HM1 cells against Jurkat and HaCaT cells were blocked by anti-TRAIL mAb but not by anti-FasL mAb, and bystander cytotoxic activities of anti-CD3-stimulated HK12 and 4HM1 cells were abolished by the combination of anti-TRAIL and anti-FasL mAbs. These results indicate a differential regulation of TRAIL and FasL expression on human CD4+ T cell clones and that TRAIL constitutes an additional pathway of T cell-mediated cytotoxicity.


A prediction model to identify patients without a concerning intraabdominal diagnosis.
Patients with abdominal diagnoses constitute 5% to 10% of all emergency department (ED) presentations. The goal of this study is to identify which of these patients will have a nonconcerning diagnosis based on demographic, physical examination, and basic laboratory testing. Consecutive patients from July 2013 to March 2014 discharged with a gastrointestinal (GI) diagnosis who presented to an urban, university-affiliated ED were identified. The cohort was split into a derivation set and a validation set. Using univariate and multivariable logistic regression analysis, a risk score was created based on the deviation data and then tested on the validation data. There were 8852 patients with a GI diagnosis during the study period. A total of 7747 (87.5%) of them had a nonconcerning diagnosis. The logistic regression model identified 13 variables that predict a concerning GI diagnosis and created a scoring system ranging from 0 to 20. The area under the receiver operating characteristic was 0.81. When dichotomized at greater than or equal to 7 vs less than 7, the risk score has a sensitivity of 91% (95% confidence interval [CI], 88-94), specificity of 46% (95% CI, 44-48), positive predictive value of 17% (95% CI, 15-19) and negative predictive value of 98% (95% CI, 97-99). One can determine with a high degree of certainty, based only on an initial evaluation and screening laboratory work (excluding radiology) whether a patient who presents with a GI-related complaint has a nonconcerning diagnosis. This model could be used as a tool to aid in quality assurance when reviewing patients discharged with GI complaints and with future study, as a secondary triage instrument in a crowded ED environment, and aid in resource allocation.


Expression of an anther-specific chalcone synthase-like gene is correlated with uninucleate microspore development in Nicotiana sylvestris.
Two cDNA clones, specifically expressed in Nicotiana sylvestris anthers during uninucleate microspore development, were isolated using a subtractive hybridization approach. Sequence analysis showed that one of them, NSCHSLK, displayed a high level of similarity to several anther-specific chalcone synthase-like (CHSLK) proteins and an ORF from chromosome I of Arabidopsis thaliana. A lower, but significant, similarity to chalcone synthases and closely related enzymes (CHSRE) was also detected. The structure of the nschslk gene was found to be typical of the chalcone (chs)/stilbene (sts) synthase family. Expression of NSCHSLK mRNA was confined to microspores and tapetal cells. UV-irradiation or infection with Phytophthora parasitica var. nicotianae of transgenic Nicotiana benthamiana plants carrying a chimeric nschslk/GUS gene indicated that the nschslk promoter exhibits the same anther-specific, developmentally regulated expression pattern. Comparison of CHSRE and CHSLK polypeptide sequences revealed some important similarities and differences between the two groups. The data presented in this study, suggest that the anther-specific chslk genes represent a separate sub-family of plant polyketide synthases related to chs/sts in terms of gene structure, polypeptide sequence and the possible catalytic mechanism, but differing in substrate/product specificity. The putative role of CHSLK enzymes in anther development and particularly in exine synthesis is discussed.


Detection techniques for validating Doppler estimates in heterodyne lidar.
We investigate the ability of detection techniques based on the likelihood ratio to discriminate between heterodyne lidar Doppler estimates at low signal levels using examples generated by simulation. The distinction between estimates that are regarded as acceptable and as spurious is based on the Cramer-Rao lower bound. The conditional false alarm probability, which ordinarily describes recording detection of a signal when none is present, is then found to be an approximate upper bound on the probability of selection of a spurious estimate. The method is superior theoretically to similar techniques based on detection functions other than the likelihood ratio. The likelihood ratio also provides a basis for reprocessing rejected data in the light of contextual information provided by those estimates that are accepted.


Primary squamous cell carcinoma of the ampulla of Vater.
Squamous carcinoma of the ampulla of Vater is a very rare tumor with only three cases been reported so far. Here, we report the case of a 68-year-old man who presented with painless obstructive jaundice, general fatigue, loss of appetite and weight loss. Laboratory tests revealed hypochromic anemia. Total and direct bilirubin, alkaline phosphatase, liver enzymes, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) were all elevated. Abdominal ultrasonography and computed tomography showed a distended gallbladder, dilatation of the intra- and extra-hepatic bile ducts and enlargement of the pancreatic head. Endoscopic retrograde cholangiopancreatography revealed a bulging papilla with infiltrative growth at the ampulla of Vater but endoscopic biopsies were inconclusive. The patient was treated with classical Whipple's pancreaticoduodenectomy. Histopathological examination showed a moderately differentiated squamous cell carcinoma. Multiple serial sectioning of the tumor specimen failed to detect an adenomatous component. Regional lymph nodes and resection margins were free of tumor and the disease was classified as stage IIA (T3N0M0) according to the TNM system. Adjuvant treatment was not given. Despite curative resection, multiple liver metastases developed after four months and the patient succumbed to progressive hepatic failure 5 months after the operation. Primary pure squamous cell carcinoma of the ampulla of Vater is a very rare histological type of carcinoma. Clinical characteristics and optimal treatment are obscure. Primary surgical treatment with curative intent should be performed although this type of carcinoma associates with dismal prognosis.


Steroid induced osteonecrosis: An analysis of steroid dosing risk.
Osteonecrosis is a serious condition involving bone destruction that frequently requires surgical treatment to rebuild the joint. While there is an abundance of literature documenting corticosteroid related osteonecrosis, there is no consensus as to the relative risk of osteonecrosis after administration of steroids via parenteral, oral, topical, inhaled and other routes. This risk is an important prognostic indicator because identification and conservative intervention can potentially reduce morbidity associated with aggressive surgical treatment of osteonecrosis. This paper provides insight into establishing guidelines related to the risk of developing osteonecrosis as a result of corticosteroid use. Case studies, retrospective studies and prospective studies in humans on different corticosteroids and varied dosages were assessed. Most cases of osteonecrosis are secondary to systemically administered corticosteroids and/or high dose daily therapy, particularly in patients with underlying comorbidities including connective tissue diseases, hyperlipidemia, or previous trauma. Previous case reports of osteonecrosis related to inhaled or topical use of steroids are complicated by the fact that in the great majority of cases, the patients are also treated with systemic steroids prior to the development of osteonecrosis. Based on the literature, a set of recommendations regarding the risk of osteonecrosis in patients on steroids was formulated.


[Microcomputer simulation of nuclear magnetic resonance imaging contrasts].
The high information content of magnetic resonance images is due to the multiplicity of its parameters. However, this advantage introduces a difficulty in the interpretation of the contrast: an image is strongly modified according to the visualised parameters. The author proposes a micro-computer simulation program. After recalling the main intrinsic and extrinsic parameters, he shows how the program works and its interest as a pedagogic tool and as an aid for contrast optimisation of images as a function of the suspected pathology.


Inhalation anesthesia without any intravenous management for pediatric proton beam therapy.
Proton beam therapy is an oncological treatment, argued to be an appropriate tumor irradiation technique for childhood solid tumors. Due to its duration and the need for immobility, many children require anesthesia for proton therapy sessions. As not many centers in the world provide this therapy, there is little published research about pediatric anesthesia for these cases, and the available data suggest a preference for intravenous anesthesia or combined intravenous and inhalation anesthesia. We conducted this study with the aim of describing and analyzing the inhalation anesthetic management of children undergoing proton therapy at our medical center, comparing our results with studies that have followed different anesthetic protocols. We reviewed two major databases (Web of Science and Scopus) to find papers that had addressed, to date, anesthesia for pediatric proton therapy. To describe our anesthetic management, we included all pediatric patients treated with proton therapy under anesthesia in our center between June 2020 and August 2021. The characteristics of the patients, their diagnoses, treatments, airway management, drugs administered, duration of induction, and recovery from anesthesia, and adverse effects where all recorded. All anesthesiologists followed a strict anesthetic protocol based only on inhalational anesthesia with sevoflurane delivered via laryngeal mask airway. Of the total of 1082 papers found in Web of Science and Scopus on pediatric proton therapy, 11 have addressed its anesthetic management, using intravenous or combined intravenous and inhalation anesthesia. Between June 2020 and August 2021, 31 children were anesthetized in our center to receive proton therapy under inhalational anesthesia (total number of sessions: 873). The mean anesthesia induction time was 4.1 min (SD = 0.7, 95% CI [3.9, 4.4]). The mean anesthesia recovery time was 13.8 min (SD = 4.1, 95% CI [12.3, 15.3]). The percentage of non-serious adverse effects was 0.7% (Clopper-Pearson 95% CI [0.3, 1.5]). The percentage of serious adverse effects was 0.1% (Clopper-Pearson 95% CI [0, 0.6]), without statistically significant difference with other published works with different anesthetic approaches. Inhalation anesthesia without any intravenous management for pediatric proton therapy is, in our experience, an effective technique with a complication rate similar to other anesthetic approaches.


Eye movements in vestibular disorders.
The differential diagnosis of patients with vestibular symptoms usually begins with the question: is the lesion central or is it peripheral? The answer commonly emerges from a careful examination of eye movements, especially when the lesion is located in otherwise clinically silent areas of the brain such as the vestibular portions of the cerebellum (flocculus, paraflocculus which is called the tonsils in humans, nodulus, and uvula) and the vestibular nuclei as well as immediately adjacent areas (the perihypoglossal nuclei and the paramedian nuclei and tracts). The neural circuitry that controls vestibular eye movements is intertwined with a larger network within the brainstem and cerebellum that also controls other types of conjugate eye movements. These include saccades and pursuit as well as the mechanisms that enable steady fixation, both straight ahead and in eccentric gaze positions. Navigating through this complex network requires a thorough knowledge about all classes of eye movements to help localize lesions causing a vestibular disorder. Here we review the different classes of eye movements and how to examine them, and then describe common ocular motor findings associated with central vestibular lesions from both a topographic and functional perspective.


Strain Relaxation in CVD Graphene: Wrinkling with Shear Lag.
We measure uniaxial strain fields in the vicinity of edges and wrinkles in graphene prepared by chemical vapor deposition (CVD), by combining microscopy techniques and local vibrational characterization. These strain fields have magnitudes of several tenths of a percent and extend across micrometer distances. The nonlinear shear-lag model remarkably captures these strain fields in terms of the graphene-substrate interaction and provides a complete understanding of strain-relieving wrinkles in graphene for any level of graphene-substrate coherency.


Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study.
Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts. A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year. Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years. In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy.


What deserves our respect? Reexamination of respect for autonomy in the context of the management of chronic conditions.
The global increase in patients with chronic conditions has led to increased interest in ethical issues regarding such conditions. A basic biomedical principle-respect for autonomy-is being reexamined more critically in its clinical implications. New accounts of this basic principle are being proposed. While new accounts of respect for autonomy do underpin the design of many public programs and policies worldwide, addressing both chronic disease management and health promotion, the risk of applying such new accounts to clinical setting remain understudied. However, the application of new accounts of respect for autonomy to clinical settings could support disrespectful attitudes toward or undue interference with patients with chronic conditions. Reconsidering autonomy and respect using Kantian accounts, this paper proposes respect for persons as an alternative basic bioethical principle to respect for autonomy. Unlike the principle of respect for persons in the Belmont Report, our principle involves respecting any patient's decisions, behaviors, emotions, or life-style regardless of his or her "autonomous" capabilities. Thus, attitudes toward patients should be no different irrespective of the assessment of their decisional or executive capabilities.


Curvature and size effects hinder halogen bonds with extended π systems.
Curvature and size effects in halogen interactions with extended aromatic species have been evaluated, employing computational methods, in dimers formed by dihalogens Cl2, Br2 and I2 with both planar (coronene and circumcoronene) and curved (corannulene, sumanene and C60) aromatic systems. The main controlling factor in these interactions is dispersion, so they become stronger as the size of the halogen grows. The nature of the interaction with the halogen changes depending on the curvature and the extension of the aromatic system. As the aromatic species becomes larger, parallel stacked structures are favoured by dispersion increases over halogen bonded ones. Parallel dimers by the concave side are also favoured as the curvature of the aromatic species increases, while the effect is the opposite by the convex side. Overall, halogen bond interactions are not favoured for large planar or curved aromatic systems; only by the convex face of the most curved structures the dispersion contribution decreases enough so as to make halogen bonded structures competitive with parallel stacked ones.