Multidisciplinary approach for improved outcomes in secondary cranial reconstruction: introducing the pericranial-onlay cranioplasty technique.
Although materials for secondary cranial reconstruction have evolved with time, the overall approach in terms of bone flap/implant reconstruction after necessary delay has remained constant. To present our cases series of 50 consecutive secondary cranial reconstruction patients and to describe a multidisciplinary cranioplasty approach developed to reduce morbidity, to minimize infection, and to improve aesthetic appearance. Standard technique teaches us to place the bone flap and/or alloplastic implant directly over the dura or dural protectant after scalp flap re-elevation. However, this procedure is fraught with high complication rates, including infection. While raising the previously incised scalp flap overlying the full-thickness calvarial defect, the dissection is performed within the loose areolar tissue plane beneath the galea aponeurosis, thus leaving vascularized pericranium intact over the dura. A total of 50 consecutive patients were treated by the senior author encompassing 46 cranioplasties using the pericranial-onlay approach, along with 4 isolated temporal soft tissue reconstructions with liquid poly-methyl-methacrylate. Of the 46 cranioplasties (> 5 cm), only 1 autologous bone flap developed deep infection necessitating bone flap removal (1 of 46, 2.17%; 95% confidence interval, 0.003-11.3). None of the alloplastic custom implants placed have developed any infection requiring removal. This multidisciplinary approach illustrated in our case series, including our "pericranial-onlay" technique described here for the first time, has the potential to improve patient outcomes, to decrease perioperative morbidity, and to minimize costs associated with postoperative infections after secondary cranial reconstruction.


Diversity of tryptophan halogenases in sponges of the genus Aplysina.
Marine sponges are a prolific source of novel enzymes with promising biotechnological potential. Especially halogenases, which are key enzymes in the biosynthesis of brominated and chlorinated secondary metabolites, possess interesting properties towards the production of pharmaceuticals that are often halogenated. In this study we used a polymerase chain reaction (PCR)-based screening to simultaneously examine and compare the richness and diversity of putative tryptophan halogenase protein sequences and bacterial community structures of six Aplysina species from the Mediterranean and Caribbean seas. At the phylum level, bacterial community composition was similar amongst all investigated species and predominated by Actinobacteria, Chloroflexi, Cyanobacteria, Gemmatimonadetes, and Proteobacteria. We detected four phylogenetically diverse clades of putative tryptophan halogenase protein sequences, which were only distantly related to previously reported halogenases. The Mediterranean species Aplysina aerophoba harbored unique halogenase sequences, of which the most predominant was related to a sponge-associated Psychrobacter-derived sequence. In contrast, the Caribbean species shared numerous novel halogenase sequence variants and exhibited a highly similar bacterial community composition at the operational taxonomic unit (OTU) level. Correlations of relative abundances of halogenases with those of bacterial taxa suggest that prominent sponge symbiotic bacteria, including Chloroflexi and Actinobacteria, are putative producers of the detected enzymes and may thus contribute to the chemical defense of their host.


Differentiated regions of human placental cell surface associated with attachment of chorionic villi, phagocytosis of maternal erythrocytes and syncytiotrophoblast repair.
Scanning electron micrographs of human placental cell surface show: (1) Differentiated zones of trophoblast which may be covered by fewer 'microvilli' than the adjacent syncytial cell surface and which extend as a narrow, usually distal protrusion of the chorionic villus. This narrow outgrowth terminates as a fractured end. Presumably since preparations were obtained from therapeutic terminations of pregnancy or Caesarian deliveries these broken ends represent the yield point in the anchoring 'villi' ruptured as a result of surgery. Similar anchoring 'villi' with fractured ends were observed in unfixed material with the use of Nomarski interference contrast microscopy. (2) It appears that, during apparent phagocytic uptake of maternal erythrocytes by syncytiotrophoblast, cell surface lining the forming vacuole still retains an irregular microvillous surface. This observation indicates the potential location of phagocytosis receptors for red blood cells in the placental cell surface. (3) Areas of human placenta which appears to have been damaged and may be undergoing repair exhibit masses of cells with conspicuous microvillar cell surfaces. The origin of these cells is discussed in relation to the usual processes of syncytiotrophoblast formation.


Achieving improvement through quality: an evaluation of key factors in the implementation process.
Quality, audit and standard setting are major issues on the present day nursing and health care agenda. Considerable time, energy and resources have been invested in developing and implementing a range of different quality and audit systems, yet there is limited evidence to date to suggest that they are having any significant impact in terms of changing practice and improving patient care. This paper will present the results of a study undertaken to evaluate the implementation of three of the most common nursing quality systems used in the United Kingdom: Monitor, Qualpacs and the dynamic standard setting system (DySSSy). In each case, the focus was on identifying key factors in the process of implementation that could predict positive programme outcomes--defined in terms of acceptance by clinical nursing staff and perceived impact on the quality of patient care. The study adopted a three-stage evaluation design, with three distinct levels of investigation and analysis, and utilized a range of descriptive and exploratory methods. In total, 14 sites implementing one of the three nursing quality systems were studied. Additional data, derived from individuals' experiences of implementing quality in nursing, were used to enhance and validate the findings. The results indicated a number of important system-related, contextual and practical issues of implementation. These were underpinned by two key factors, defined as ownership for quality and action to improve. However, most present day nursing quality programmes appear to be failing to embrace these two concepts simultaneously. The paper will conclude by discussing the implications of these findings for future developments in nursing and health care quality improvement.


Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis.
Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.


Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG.
(18)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine ((18)F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The (18)F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of (18)F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood. Healthy New Zealand White rabbits were studied with (18)F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of (18)F-LMI1195. Imaging was performed under norepinephrine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of (11)C-hydroxyephedrine and (123)I-metaiodobenzylguanidine ((123)I-MIBG) was examined by PET and planar scintigraphy, respectively. Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for (11)C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and (18)F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased (11)C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P < 0.001), whereas (18)F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac (123)I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant). In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of (18)F-LMI1195, (11)C-hydroxyephedrine, and (123)I-MIBG in rabbit hearts. (11)C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, (18)F-LMI1195 and (123)I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.


Environmental harshness and unpredictability, life history, and social and academic behavior of adolescents in nine countries.
Safety is essential for life. To survive, humans and other animals have developed sets of psychological and physiological adaptations known as life history (LH) tradeoff strategies in response to various safety constraints. Evolutionarily selected LH strategies in turn regulate development and behavior to optimize survival under prevailing safety conditions. The present study tested LH hypotheses concerning safety based on a 6-year longitudinal sample of 1,245 adolescents and their parents from 9 countries. The results revealed that, invariant across countries, environmental harshness, and unpredictability (lack of safety) was negatively associated with slow LH behavioral profile, measured 2 years later, and slow LH behavioral profile was negatively and positively associated with externalizing behavior and academic performance, respectively, as measured an additional 2 years later. These results support the evolutionary conception that human development responds to environmental safety cues through LH regulation of social and learning behaviors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Evaluation of a novel intervention to reduce burnout in doctors-in-training using self-care and digital wellbeing strategies: a mixed-methods pilot.
Burnout for doctors-in-training is increasingly cause for concern. Our objectives were to assess the feasibility, acceptability and impact of a novel intervention to reduce burnout and improve wellbeing. This is the first wellbeing intervention for medical doctors to include strategies for work-life boundary management and digital wellbeing. Twenty-two doctors participated in face-to-face workshops which included group discussion of challenges experienced and strategies to enhance self-care and wellbeing. A pre-post-test mixed-methods evaluation was undertaken. Questionnaire measures were the Oldenburg Burnout Inventory, Warwick-Edinburgh Mental Wellbeing Scale and the boundary control subscale of the Work-Life Indicator (i.e., the degree of perception of control of the boundaries between work and personal life). Paired t-tests examined whether there were statistically significant differences. Eleven doctors also participated in post-intervention semi-structured interviews. Transcripts were analysed using thematic analysis. The intervention was well-received, with all trainees finding the workshop useful and saying they would recommend it to others. At baseline most participants had scores indicative of burnout on both the disengagement (82%) and exhaustion (82%) subscales of the Oldenburg Burnout Inventory. One month post-intervention, participants had a statistically significant reduction in burnout (both disengagement and exhaustion) and improvement in boundary control. Wellbeing scores also improved, but differences were not statistically significant. Qualitative analysis indicated participants had welcomed a safe space to discuss stressors and many had implemented digital wellbeing strategies to manage their smartphone technology, and increased self-care such as mindfulness practice and walking in green space. The intervention reduced burnout and improved boundary control. We suggest that having protected time for doctors to share personal experiences, adopt digital wellbeing and self-care strategies are effective tools to support doctors' wellbeing and should be investigated further.


Detection of peripheral artery disease by duplex ultrasonography among hemodialysis patients.
Peripheral arterial disease (PAD) is a known predictor of cardiovascular morbidity and mortality among hemodialysis patients. Although ankle-brachial BP index (ABI) is a simple and reliable test for PAD screening, its sensitivity has been suggested to decrease among dialysis patients. We performed a cross-sectional outpatient cohort study to examine prevalence of PAD among hemodialysis patients using duplex ultrasonography of the lower extremity artery. We also evaluate the influence of increased arterial stiffness on impaired accuracy of ABI for PAD screening. Of 315 total patients, 23.8% had PAD. PAD was associated with younger age, diabetes, current smoking, atherosclerotic comorbidities, increased total cholesterol levels, increased triglyceride levels, and lower Kt/V. The receiver operating characteristic analysis (area under the receiver operating characteristic curve = 0.846) showed that sensitivity and specificity of ABI values for PAD were 49.0 and 94.8%, respectively. An ABI cut-off value of 1.05 resulted in the best sensitivity (74.5%) and specificity (84.4%). There was a significant difference in sensitivity of ABI levels <0.9 for detecting PAD among patients in different brachial-ankle pulse wave velocity quartiles. In patients with the highest brachial-ankle pulse wave velocity quartile, PAD was most prevalent (46.5%), and ABI had the highest accuracy in detecting PAD (area under the curve, 0.933). These results suggest that duplex ultrasonography was a useful tool for screening asymptomatic PAD among hemodialysis patients and that the diagnostic value of ABI for PAD was affected by various factors.


An initial comparison of nine centres registering patients with the UK National Barrett's Oesophagus Registry (UKBOR).
Initial data from the first nine hospitals registering at least 50 patients each with UKBOR were analysed. This involved 2102 Barrett's oesophagus (BO) cases (M1261:F841), mean 234 patients per centre (range 73-636) and M:F ratio 1.5 (range 1.1-2.3). There was an equal geographical distribution of the hospitals, three each in the north of the country (N), Midlands (Mid) and the south of the country (S). The catchment populations varied from 145,000 to 450,000. The M:F ratio for N, Mid and S was 1.6, 1.3, 1.7, respectively. The mean age at diagnosis in males was 62.0 years (range 53.2-66.3) and in females 67.6 years (range 59.3-73.4), with little geographical variation. The age distribution varied somewhat between the centres; the peak age for males being 40-49 years in one northern hospital, 60-69 years in seven others and 70-79 years in one hospital. For females it was 60-69 years and 70-79 years in each of four hospitals, and 80-89 years in one. The BO diagnosis rate in the under 50s was fairly constant; F mean 14% (range 0-23%); M (eight centres) mean 23% (range 16-27%). However, in one northern centre it was much higher (43%). Information on patients with a diagnosis of oesophageal adenocarcinoma (AC) was available from seven centres. A total of 59 AC were diagnosed (M44:F15, ratio 2.9). The overall mean rate of AC in BO was 3.6% (range 0.5-7.5%). Minor variations in BO patient characteristics may have been due to the hospitals' different policies on diagnostic and reporting criteria. However, the much higher percentage of men under age 50 in the one N centre may reflect a genuine difference in diet and lifestyle, or possibly genetic susceptibility.


Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial.
The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior. The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals. In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo. In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.


Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared with prednisolone.
Glucocorticoids are widely prescribed to treat autoimmune and inflammatory diseases. Although they are extremely potent, their utility in clinical practice is limited by a variety of adverse side effects. Development of compounds that retain the potent immunomodulating and anti-inflammatory properties of classic glucocorticoids while exhibiting reduced adverse actions is therefore a priority. Using heavy water labeling and mass spectrometry to measure fluxes through multiple glucocorticoid-responsive, disease-relevant target pathways in vivo in mice, we compared the effects of a classic glucocorticoid receptor (GR) ligand, prednisolone, with those of a novel arylpyrazole-based compound, L5 {[1-(4-fluorophenyl)-4a-methyl-5,6,7,8-tetrahydro-4H-benzo[f]indazol-5-yl]-[4-(trifluoromethyl)phenyl]methanol}. We show for the first time that L5 exhibits clearly selective actions on disease-relevant pathways compared with prednisolone. Prednisolone reduced bone collagen synthesis, skin collagen synthesis, muscle protein synthesis, and splenic lymphocyte counts, proliferation, and cell death, whereas L5 had none of those actions. In contrast, L5 was a more rapid and potent inhibitor of hippocampal neurogenesis than prednisolone, and L5 and prednisolone induced insulin resistance equally. Administration of prednisolone or L5 increased expression comparably for one GR-regulated gene involved in protein degradation in skeletal muscle (Murf1) and one GR-regulated gluconeogenic gene in liver (PEPCK). In summary, L5 dissociates the pleiotropic effects of the GR ligand prednisolone in intact animals in ways that neither gene expression nor cell-based models were able to fully capture or predict. Because multiple actions can be measured concurrently in a single animal, this method is a powerful systems approach for characterizing and differentiating the effects of ligands that bind nuclear receptors.


Cellular proliferation in proximal and distal rat colon during 1,2-dimethylhydrazine-induced carcinogenesis.
Sequential changes in proliferative parameters in proximal and distal colonic crypts were studied during 1,2-dimethylhydrazine-induced carcinogenesis using [3H]thymidine autoradiography as a probe. 1,2-dimethylhydrazine (20 mg/kg) and vehicle (ethylenediaminetetraacetic acid) control rats received weekly s.c. injections for 20 wk. All animals received a pulse of [3H]thymidine before death at weeks 2, 6, 10, 16, 22, 26, or 30. In addition, 8 animals unexposed to 1,2-dimethylhydrazine or vehicle served as baseline controls. Dramatic regional differences were noted in the baseline controls. Crypt length, labeling index, and proliferative zone size were all significantly greater distally than proximally (p less than 0.05), whereas the labeling index of the proliferative zone tended to be enhanced proximally. During 1,2-dimethylhydrazine treatment the crypt length, labeling index, and proliferative zone size increased in both regions. As these parameters changed in parallel, the differences between proximal and distal colon did not change significantly during carcinogenesis. Actual tumor formation did differ, however, with tumors appearing earlier and in greater abundance in the distal colon. These findings show similar proliferative changes in both the proximal and distal colon during 1,2-dimethylhydrazine treatment and indicate that the enhanced baseline proliferative state of the distal colon compared with the proximal colon must be considered in the process of tumor formation.


Behavioural learning-induced increase in spontaneous GABAA-dependent synaptic activity in rat striatal cholinergic interneurons.
Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent motor behaviours. They are considered to correspond to the tonically active neurons (TANs) of the primate striatum, which phasically decrease their discharge at the presentation of reward-related sensory stimuli. The origin of this response is still poorly understood. Therefore, in the present paper, we have investigated whether synaptic changes establish in cholinergic interneurons from young rats that have learned a rewarded, externally cued sensorimotor task. Corticostriatal slices were prepared from both control and trained rats. No significant change in intrinsic membrane properties and evoked synaptic activity was observed in cholinergic interneurons, nor the responsiveness to exogenously applied dopaminergic and glutamatergic agonists was modified. Conversely, an increased occurrence of spontaneous bicuculline-sensitive depolarizing postsynaptic potentials (sDPSP) was recorded. The frequency of the GABAA-mediated sDPSP was increased in comparison to not-conditioned rats. Overall, these results suggest that after learning a rewarded sensorimotor paradigm an increased GABA influence develops on cholinergic interneurons. The origin of this effect might be searched in collaterals of GABAergic output spiny neurons as well as in GABAergic striatal interneurons impinging onto cholinergic interneurons. This intrastriatal mechanism might be involved in the phasic suppression of discharge of TANs at the presentation of reward-related sensory stimuli.


Physical and energy requirements of competitive swimming events.
The aquatic sports competitions held during the summer Olympic Games include diving, open-water swimming, pool swimming, synchronized swimming, and water polo. Elite-level performance in each of these sports requires rigorous training and practice to develop the appropriate physiological, biomechanical, artistic, and strategic capabilities specific to each sport. Consequently, the daily training plans of these athletes are quite varied both between and within the sports. Common to all aquatic athletes, however, is that daily training and preparation consumes several hours and involves frequent periods of high-intensity exertion. Nutritional support for this high-level training is a critical element of the preparation of these athletes to ensure the energy and nutrient demands of the training and competition are met. In this article, we introduce the fundamental physical requirements of these sports and specifically explore the energetics of human locomotion in water. Subsequent articles in this issue explore the specific nutritional requirements of each aquatic sport. We hope that such exploration will provide a foundation for future investigation of the roles of optimal nutrition in optimizing performance in the aquatic sports.


Adult Patients' Experiences of Nursing Care Dependence.
Care dependence can be associated with suffering and humiliation. Nurses' awareness of patients' perception of care dependence is crucial to enable them in helping the dependent persons. This study aimed to describe adult patients' experience of nursing care dependence. A metasynthesis was conducted to integrate qualitative findings from 18 studies published through December 2014 on adult patients' experiences of care dependency. Procedures included the Johanna Briggs Institute approach for data extraction, quality appraisal, and integration of findings. The experience of dependence revealed the concept of the embodied person, particularly in relation to care of the physical body. The relationship between the individual and nurses within the context of care had a major impact for dependent patients. When the care relation was perceived as positive, the experience led to the development of the person in finding new balances in life, but when it was perceived as negative, it increased patient' suffering. Care dependence is manifested mostly as bodily dependence and is consistent with its relational nature. The nurse-patient relationship is important to the dependent patients' experience. A greater understanding of patients' experiences of dependence is crucial to enable nurses in improving care and decreasing patient suffering.


Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker.
The widespread use of prostate-specific antigen (PSA) screening has had a tremendous impact on all aspects of the management of prostate carcinoma. Although PSA-based screening has resulted in a stage migration to more organ-confined tumors at the time of diagnosis, and has been temporally associated with a decrease in prostate carcinoma mortality, PSA screening is imperfect. A recent analysis of results from the Prostate Cancer Prevention Trial (PCPT) has provided insight into the positive predictive value of PSA in the so-called "normal" range. The history of the discovery, initial studies, and subsequent widespread application of PSA screening is reviewed. The application of PSA for screening preceded the development of current prostate biopsy techniques and an upper limit of normal was established without complete disease ascertainment. More recent modifications of PSA-based screening have been adopted clinically without sufficient validation. With current methods, overdiagnosis of clinically unimportant disease almost certainly occurs and high-grade, aggressive disease may not be detected sufficiently early to allow successful treatment. To the authors' knowledge, the optimal upper limit of normal for PSA for prostate carcinoma screening is unknown. New biomarkers of disease are needed; these must be linked with disease prognosis and must be validated in rigorously designed clinical trials.


On the convergence of generalized simultaneous iterative reconstruction algorithms.
In this paper, we generalize the widely used simultaneous block iterative reconstruction algorithm and show that it converges, at a linear rate, to a weighted least-squares and weighted minimum-norm reconstruction. Our theoretical result provides a much simpler proof of the convergence properties obtained by Jiang and Wang and covers a much more general class of algorithms. The frequency domain iterative reconstruction algorithm is then introduced as a special application of our theory.


CHROMA: consensus-based colouring of multiple alignments for publication.
CHROMA annotates multiple protein sequence alignments by consensus to produce formatted and coloured text suitable for incorporation into other documents for publication. The package is designed to be flexible and reliable, and has a simple-to-use graphical user interface running under Microsoft Windows. Both the executables and source code for CHROMA running under Windows and Linux (portable command-line only) are freely available at http://www.lg.ndirect.co.uk/chroma. Software enquiries should be directed to firstname.lastname@example.com.


Unambiguous 3D measurement from speckle-embedded fringe.
This paper proposes a novel phase-shifting method for fast, accurate, and unambiguous 3D shape measurement. The basic idea is embedding a speckle-like signal in three sinusoidal fringe patterns to eliminate the phase ambiguity, but without reducing the fringe amplitude or frequency. The absolute depth is then recovered through a robust region-wise voting strategy relying on the embedded signal. Using the theoretical minimum of only three images, the proposed method greatly facilitates the application of phase shifting in time-critical conditions. Moreover, the proposed method is resistant to the global illumination effects, as the fringe patterns used are with a single high frequency. Based on the proposed method, we further demonstrate a real-time, high-precision 3D scanning system with an off-the-shelf projector and a commodity camera.


Aggression, grooming and group-level cooperation in white-faced capuchins (Cebus capucinus): insights from social networks.
The form of animal social systems depends on the nature of agonistic and affiliative interactions. Social network theory provides tools for characterizing social structure that go beyond simple dyadic interactions and consider the group as a whole. We show three groups of capuchin monkeys from Barro Colorado Island, Panama, where there are strong connections between key aspects of aggression, grooming, and proximity networks, and, at least among females, those who incur risk to defend their group have particular "social personalities." Although there is no significant correlation for any of the network measures between giving and receiving aggression, suggesting that dominance relationships do not follow a simple hierarchy, strong correlations emerge for many measures between the aggression and grooming networks. At the local, but not global, scale, receiving aggression and giving grooming are strongly linked in all groups. Proximity shows no correlation with aggression at either the local or the global scale, suggesting that individuals neither seek out nor avoid aggressors. Yet, grooming has a global but not local connection to proximity. Extensive groomers who tend to direct their efforts at other extensive groomers also spend time in close proximity to many other individuals. These results indicate the important role that prosociality plays in shaping female social relationships. We also show that females who receive the least aggression, and thus pay low costs for group living, are most likely to participate in group defense. No consistent "social personality" traits characterize the males who invest in group defense.


Persistent directional cell migration requires ion transport proteins as direction sensors and membrane potential differences in order to maintain directedness.
Ion transport proteins generate small electric fields that can induce directional cell motility; however, little is known about their mechanisms that lead to directedness. We investigated Na, K-ATPase (NaKA) and Na+/H+ exchanger isoforms (NHE1 and 3) in SaOS-2 and Calvarial osteoblasts, which present anode- and cathode- directed motility, during electrotaxis. Significant colocalizations of NaKA with vinculin and pNHE3 with ß-actin were observed to occur at the leading edges of cells. The directedness were attenuated when NaKA or NHE3 was inhibited, confirming their implication in directional sensing. Depending on the perceived direction, a divergent regulation in PIP2 levels as a function of NHE3 and NaKA levels was observed, suggesting that PIP2 may act as a spatiotemporal regulator of the cell membrane during electrotaxis. Moreover, at the same places where pNHE3 accumulates, bubble-shaped H+ clouds were observed, suggesting a physio-mechanical role for NHE3. The cell membrane becomes hyperpolarized at the front and depolarized at the back, which confirms NaKA activity at the leading edge. We suggest a novel role for both NaKA and NHE3 that extends beyond ion translocation and conclude that they can act as directional sensors and Vmem as a regulatory cue which maintain the persistent direction in electrotaxis.


Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract.
The KCNQI potassium channel alpha-subunit can associate with various KCNE beta-subunits that drastically influence channel gating. Here we show that in the mouse gastrointestinal tract KCNQ1 is prominently expressed in stomach, small intestine and colon, while KCNE3 is expressed in the colon and to a lesser extent in small intestine. Immunostaining revealed that KCNQ1 colocalizes with KCNE3 in the basolateral membranes of crypt cells of the colon and small intestine. Together with the previously shown electrophysiological properties of KCNQ1/KCNE3 channels, this strongly suggests that they form the basolateral potassium conductance that is required for transepithelial cAMP-stimulated chloride secretion. In the stomach, KCNQ1 is expressed together with the H+/K+-ATPase in the luminal membrane of acid-secreting parietal cells of gastric glands. KCNE2, but neither KCNE1 nor KCNE3 was detected in the stomach by Northern analysis. Similar to KCNQ1, KCNE2 was present in gastric glands in only a subset of cells that probably represent parietal cells. The coexpression of KCNQ1 and KCNE2 in HEK293 cells yielded potassium currents that were open at resting voltages, suggesting that these heteromeric channels may underlie the apical potassium conductance in acid-secreting parietal cells that is necessary for the recycling of potassium ions during acid secretion via the H+/K+-ATPase.


Learning to attain an advanced level of professional responsibility.
After graduation, nurse practitioner students are expected to be capable of providing complex, evidence-based nursing care independently, combined with standardized medical care. The students who follow work-study programs have to develop their competencies in a healthcare environment dominated by efficiency policies. This study aims to explore nurse practitioner students' perceptions of their professional responsibility for patient care. This qualitative interpretative study entails a content analysis of 46 reflective case studies written by nurse practitioner students. The students felt responsible for the monitoring of patients' health status, attending to psychosocial problems, emphasizing compliance, and optimizing the family's role as informal caregivers. At the same time, students struggled to understand the complexities of their patients' needs, and they had difficulty applying their knowledge and skills to complex medical, psychological, and social problems. The students' perceptions of their new responsibility were characterized by a strong focus on curative care, while psychosocial components of health and illness concerns were often overlooked. The students experienced difficulties in meeting the criteria of advanced practice nursing described in the Dutch competency framework.


Safety and Effectiveness Analysis of Kivexa® (lamivudine/abacavir sulfate) in Human Immunodeficiency Virus Infected Korean Patients.
Lamivudine and abacavir sulfate are widely used nucleoside/tide reverse transcriptase inhibitors (NRTI) backbone agents, which are recommended in major international treatment guidelines. The fixed-dose combination of lamivudine and abacavir sulfate has been developed to contribute to low pill burden of antiretroviral therapy (ART) regimen and patient adherence. A mandatory post-marketing surveillance was conducted in Korea to monitor the safety of Kivexa (lamivudine 300 mg/abacavir 600 mg). An open label, multi-center, non-interventional post-marketing surveillance was conducted to monitor the safety of Kivexa from July 2011 to July 2017 in 23 hospitals in Korea. Subjects over 12 years old taking Kivexa per prescribing information were enrolled. The primary outcome was defined as the occurrence of any adverse events during the study period. Secondary outcomes included the occurrence of adverse drug reaction, the occurrence of serious adverse events and the effectiveness of Kivexa. A total of 600 patients from 23 hospitals were enrolled within the 6 years of study. The total observation period was 1,004 person-years. Three hundred and ten patients reported 674 adverse events. The incidence of upper respiratory infection (65 cases, 10.9%) was the highest, followed by diarrhea (20 cases, 3.3%), and nausea (18 cases, 3.0%). 109 subjects reported 71 events of adverse drug reactions, and the most common reaction was nausea in 2.33% of the subjects. Thirty-one subjects reported serious adverse events, none of them were considered drug related. From the total of 600 subjects, excluding 48 subjects who were 'effectiveness unassessable' by investigators, 552 patients were eligible for the subjective effectiveness analysis. 459 (83.2%) were evaluated as 'improved'. Proportion of subjects whose human immunodeficiency virus-RNA is <50 copies/ml was 61.2% (309/505) at the beginning of observation and increased to 91.9% (464/505) at the end of study period. The post-marketing surveillance showed the safety of Kivexa in HIV-1 patients in Korea. Ischemic cardiovascular events and hypersensitivity associated with Kivexa were few. There was no significant new safety information. This data may be helpful in implementing Kivexa and lamivudine/abacavir sulfate containing drugs in Korea.


Targeting Casein Kinase 1 (CK1) in Hematological Cancers.
The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.


Progress of in vivo studies on the systemic toxicities induced by titanium dioxide nanoparticles.
Titanium dioxide nanoparticles (TiO2 NPs) are inorganic materials with a diameter of 1-100 nm. In recent years, TiO2 NPs have been used in a wide range of products, including food, toothpaste, cosmetics, medicine, paints and printing materials, due to their unique properties (high stability, anti-corrosion, and efficient photocatalysis). Following exposure via various routes including inhalation, injection, dermal deposition and gastrointestinal tract absorption, NPs can be found in various organs in the body potentially inducing toxic effects. Thus more attention to the safety of TiO2 NPs is necessary. Therefore, the present review aims to provide a comprehensive evaluation of the toxic effects induced by TiO2 NPs in the lung, liver, stomach, intestine, kidney, spleen, brain, hippocampus, heart, blood vessels, ovary and testis of mice and rats in in vivo experiments, and evaluate their potential toxic mechanisms. The findings will provide an important reference for human risk evaluation and management following TiO2 NP exposure.


Influence of caffeine on perception of effort, metabolism and exercise performance following a high-fat meal.
This study examined the effects of caffeine, co-ingested with a high fat meal, on perceptual and metabolic responses during incremental (Experiment 1) and endurance (Experiment 2) exercise performance. Trained participants performed three constant-load cycling tests at approximately 73% of maximal oxygen uptake (VO2max) for 30 min at 20 degrees C (Experiment 1, n = 8) and to the limit of tolerance at 10 degrees C (Experiment 2, n = 10). The 30 min constant-load exercise in Experiment 1 was followed by incremental exercise (15 W . min-1) to fatigue. Four hours before the first test, the participants consumed a 90% carbohydrate meal (control trial); in the remaining two tests, the participants consumed a 90% fat meal with (fat + caffeine trial) and without (fat-only trial) caffeine. Caffeine and placebo were randomly assigned and ingested 1 h before exercise. In both experiments, ratings of perceived leg exertion were significantly lower during the fat + caffeine than fat-only trial (Experiment 1: P < 0.001; Experiment 2: P < 0.01). Ratings of perceived breathlessness were significantly lower in Experiment 1 (P < 0.01) and heart rate higher in Experiment 2 (P < 0.001) on the fat + caffeine than fat-only trial. In the two experiments, oxygen uptake, ventilation, blood [glucose], [lactate] and plasma [glycerol] were significantly higher on the fat + caffeine than fat-only trial. In Experiment 2, plasma [free fatty acids], blood [pyruvate] and the [lactate]:[pyruvate] ratio were significantly higher on the fat + caffeine than fat-only trial. Time to exhaustion during incremental exercise (Experiment 1: control: 4.9, s = 1.8 min; fat-only: 5.0, s = 2.2 min; fat + caffeine: 5.0, s = 2.2 min; P > 0.05) and constant-load exercise (Experiment 2: control: 116 (88 - 145) min; fat-only: 122 (96 - 144) min; fat + caffeine: 127 (107 - 176) min; P > 0.05) was not different between the fat-only and fat + caffeine trials. In conclusion, while a number of metabolic responses were increased during exercise after caffeine ingestion, perception of effort was reduced and this may be attributed to the direct stimulatory effect of caffeine on the central nervous system. However, this caffeine-induced reduction in effort perception did not improve exercise performance.


Tibial Plafond Fractures: Changing Principles of Treatment.
Tibial plafond fractures from axial loading are high-energy injuries with significant associated soft-tissue damage. New classification methods include detailed anatomic subgroupings and highlight the soft-tissue injury. The traditional treatment of this intra-articular fracture with open reduction and internal fixation resulted in high rates of wound breakdown and infection. Treatment of these complications is lengthy and costly and not infrequently results in a poor outcome. Newer techniques using external fixation minimize disturbance of the soft-tissue envelope and have decreased these complications. Because the long-term outcome with all techniques is variable and often depends on factors beyond the surgeon's control, it is particularly important to avoid complications of initial treatment. Longer follow-up will determine whether patients treated with these techniques have a different rate of arthrosis.


Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey.
The biological mechanisms by which depression might increase risk of cardiovascular disease are not clear. Inflammation may be a key element in the development of atherosclerotic cardiovascular disease. Our objective was to determine the association between major depression and elevated C-reactive protein (CRP) level in a nationally representative cohort. We estimated the odds of elevated CRP level (>0.21 mg/mL) associated with depression in 6914 noninstitutionalized men and women (age, 18-39 years) from the Third National Health and Nutrition Examination Survey (NHANES III). The prevalence of lifetime major depression was 5.7% for men and 11.7% for women. The prevalence of elevated CRP level was 13.7% for men and 27.3% for women. A history of major depression was associated with elevated CRP level (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.20-2.24). The association between depression and CRP was much stronger among men than among women. Results were adjusted for age, African American race, body mass index, total cholesterol, log triglycerides, diabetes, systolic blood pressure, smoking status, alcohol use, estrogen use in women, aspirin use, ibuprofen use, and self-reported health status. Compared with men without a history of depression, CRP levels were higher among men who had a more recent (within 1 year) episode of depression (adjusted OR, 3.00; 95% CI, 1.39-6.48) and who had recurrent (>or=2 episodes) depression (adjusted OR, 3.55; 95% CI, 1.55-8.14). Major depression is strongly associated with increased levels of CRP among men and could help explain the increased risk of cardiovascular disease associated with depression in men.


Rab17, a novel small GTPase, is specific for epithelial cells and is induced during cell polarization.
The rab subfamily of small GTPases has been demonstrated to play an important role in the regulation of membrane traffic in eukaryotic cells. Compared with nonpolarized cells, epithelial cells have distinct apical and basolateral transport pathways which need to be separately regulated. This raises the question whether epithelial cells require specific rab proteins. However, all rab proteins identified so far were found to be equally expressed in polarized and nonpolarized cells. Here we report the identification of rab17, the first epithelial cell-specific small GTPase. Northern blot analysis on various mouse organs, revealed that the rab17 mRNA is present in kidney, liver, and intestine but not in organs lacking epithelial cells nor in fibroblasts. To determine whether rab17 is specific for epithelial cells we studied its expression in the developing kidney. We found that rab17 is absent from the mesenchymal precursors but is induced upon their differentiation into epithelial cells. In situ hybridization studies on the embryonic kidney and intestine revealed that rab17 is restricted to epithelial cells. By immunofluorescence and immunoelectron microscopy on kidney sections, rab17 was localized to the basolateral plasma membrane and to apical tubules. Rab proteins associated with two distinct compartments have been found to regulate transport between them. Therefore, our data suggest that rab17 might be involved in transcellular transport.


Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.


Biological Factors and Statistical Limitations Prevent Detection of Most Noncanonical Proteins by Mass Spectrometry.
Ribosome profiling experiments indicate pervasive translation of short open reading frames (ORFs) outside of annotated protein-coding genes. However, shotgun mass spectrometry experiments typically detect only a small fraction of the predicted protein products of this noncanonical translation. The rarity of detection could indicate that most predicted noncanonical proteins are rapidly degraded and not present in the cell; alternatively, it could reflect technical limitations. Here we leveraged recent advances in ribosome profiling and mass spectrometry to investigate the factors limiting detection of noncanonical proteins in yeast. We show that the low detection rate of noncanonical ORF products can largely be explained by small size and low translation levels and does not indicate that they are unstable or biologically insignificant. In particular, proteins encoded by evolutionarily young genes, including those with well-characterized biological roles, are too short and too lowly-expressed to be detected by shotgun mass spectrometry at current detection sensitivities. Additionally, we find that decoy biases can give misleading estimates of noncanonical protein false discovery rates, potentially leading to false detections. After accounting for these issues, we found strong evidence for four noncanonical proteins in mass spectrometry data, which were also supported by evolution and translation data. These results illustrate the power of mass spectrometry to validate unannotated genes predicted by ribosome profiling, but also its substantial limitations in finding many biologically relevant lowly-expressed proteins.


An Overview on Cyclic Fatty Acids as Biomarkers of Quality and Authenticity in the Meat Sector.
A survey was conducted to determine the content of cyclopropane fatty acids (CPFAs) and ω-cyclohexyl fatty acids (CHFAs) by using gas chromatography- mass spectrometry (GC-MS) and proton nuclear magnetic resonance (1H NMR) techniques in various meat samples from different species, including commercial samples and complex and thermally processed products (i.e., Bolognese sauce). The CPFAs concentration (as the sum of two isomers, namely dihydrosterculic acid and lactobacillic acid) in bovine meat fat (ranging between 70 and 465 mg/kg fat) was positively related to a silage-based diet, and therefore, they are potential biomarkers for monitoring the feeding system of cattle. CHFAs, such as 11-cyclohexylundecanoic and 13-cyclohexyltridecanoic acids, were only found in lipid profiles from ruminant species, and a linear trend was observed in their content, together with iso-branched fatty acids (iso-BCFAs) deriving from ruminal fermentation, as a function of bovine meat percentage in both raw and cooked minced meat. Thus, CHFAs are potential biomarkers for the assurance of the meat species and, combined with iso-BCFAs, of the beef/pork ratio even in complex meat matrices. The proposed approaches are valuable novel tools for meat authentication, which is pivotal in the management of meat quality, safety, and traceability.


The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway.
Anaerobic bacteria are present in large numbers in the airways of people with cystic fibrosis (PWCF). In the gut, anaerobes produce short-chain fatty acids (SCFAs) that modulate immune and inflammatory processes. To investigate the capacity of anaerobes to contribute to cystic fibrosis (CF) airway pathogenesis via SCFAs. Samples of 109 PWCF were processed using anaerobic microbiological culture with bacteria present identified by 16S RNA sequencing. SCFA levels in anaerobic supernatants and bronchoalveolar lavage (BAL) were determined by gas chromatography. The mRNA and/or protein expression of two SCFA receptors, GPR41 and GPR43, in CF and non-CF bronchial brushings and 16HBE14o(-) and CFBE41o(-) cells were evaluated using reverse transcription polymerase chain reaction, Western blot analysis, laser scanning cytometry, and confocal microscopy. SCFA-induced IL-8 secretion was monitored by ELISA. Fifty-seven (52.3%) of 109 PWCF were anaerobe positive. Prevalence increased with age, from 33.3% to 57.7% in PWCF younger (n = 24) and older (n = 85) than 6 years of age. All evaluated anaerobes produced millimolar concentrations of SCFAs, including acetic, propionic, and butyric acids. SCFA levels were higher in BAL samples of adults than in those of children. GPR41 levels were elevated in CFBE41o(-) versus 16HBE14o(-) cells; CF versus non-CF bronchial brushings; and 16HBE14o(-) cells after treatment with cystic fibrosis transmembrane conductance regulator inhibitor CFTR(inh)-172, CF BAL, or inducers of endoplasmic reticulum stress. SCFAs induced a dose-dependent and pertussis toxin-sensitive IL-8 response in bronchial epithelial cells, with a higher production of IL-8 in CFBE41o(-) than in 16HBE14o(-) cells. This study illustrates that SCFAs contribute to excessive production of IL-8 in CF airways colonized with anaerobes via up-regulated GPR41.


Bridging the gap between mind and body: a biobehavioral model of the effects of guided imagery on pain, pain disability, and depression.
Chronic noncancer pain (CNCP) is a common and complex disorder associated with declines in physical health and functional status, emotional well-being, and quality of life. To best address the complexity of this condition, research and clinical practice for CNCP should be guided by a framework incorporating both biologic and psychologic factors. This article presents a biobehavioral model of chronic pain that hypothesizes mechanisms related to the effectiveness of a complementary therapy, guided imagery (GI), for this population. Using the research-to-model/theory strategy, we mapped findings from published reports of interdisciplinary research into physiologic and psychologic aspects of the nature and mechanisms of pain, as well as the use of GI for pain, to build the model of GI's effects on pain, pain disability, and depression. In the model, these outcomes of GI for persons experiencing CNCP are mediated by psychologic (pain self-efficacy and pain beliefs) and physiologic (immune-mediated analgesia and sickness response) variables. A biobehavioral approach to nursing phenomena will advance understanding of health and health-related issues and has the potential to improve outcomes through delineation of mechanisms underlying relationships between psychologic and biologic factors. Increased consumer use of complementary therapies to treat pain, the current cost-driven health care system, and the mandate for evidence-based practice support the need to validate the efficacy of such therapies. This empirically derived model provides a framework for practice and research for nurses and other health care providers to promote health, function, and well-being in persons with CNCP.


Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. clinicaltrials.gov Identifier: NCT00000611.


Co-Training for Visual Object Recognition Based on Self-Supervised Models Using a Cross-Entropy Regularization.
Automatic recognition of visual objects using a deep learning approach has been successfully applied to multiple areas. However, deep learning techniques require a large amount of labeled data, which is usually expensive to obtain. An alternative is to use semi-supervised models, such as co-training, where multiple complementary views are combined using a small amount of labeled data. A simple way to associate views to visual objects is through the application of a degree of rotation or a type of filter. In this work, we propose a co-training model for visual object recognition using deep neural networks by adding layers of self-supervised neural networks as intermediate inputs to the views, where the views are diversified through the cross-entropy regularization of their outputs. Since the model merges the concepts of co-training and self-supervised learning by considering the differentiation of outputs, we called it Differential Self-Supervised Co-Training (DSSCo-Training). This paper presents some experiments using the DSSCo-Training model to well-known image datasets such as MNIST, CIFAR-100, and SVHN. The results indicate that the proposed model is competitive with the state-of-art models and shows an average relative improvement of 5% in accuracy for several datasets, despite its greater simplicity with respect to more recent approaches.


Inhibition of antibody-dependent cellular cytotoxicity and immunoglobulin synthesis by an antiserum prepared against a human B-cell Ia-like molecule.
Rabbit antisera to the human B-cell-specific antigen complex, p23,30, was used to define further the functional heterogeneity of isolated human lymphocyte subpopulations. Specific depletion of p23,30-bearing cells from Ig-negative cell populations and Ig-negative, E rosette-negative (Null) populations by either complement-mediated lysis or by physical separation on goat antirabbit Fab immunoabsorbent columns, eliminates the antibody-dependent cellular cytotoxic (ADCC) function. Furthermore, binding of anti-p23,30 serum to the effector cell surface inhibits ADCC but does not interfere with EA rosette formation. Apparently p23,30 represents a cell surface site which is distinct from the Fc receptor but which is important in the triggering of ADCC. In addition, depletion of p23,30-bearing cells from unfractionated cell populations, Ig-positive B-cell populations and Ig-negative, E rosette-negative (Null) populations eliminates the capacity of these populations to secrete immunoglobulin during subsequent culturing. Thus both the Ig-secreting cells and the ADCC effector cells within the Ig-negative, E rosette-negative (Null) population reside in the same population of cells which bears the p23,30 antigen.


Agreement between Framingham, IraPEN and non-laboratory WHO-EMR risk score calculators for cardiovascular risk prediction in a large Iranian population.
Introduction: Estimation of the risk of cardiovascular diseases (CVD), may lead to prophylactic therapies. This study aims to compare and evaluate the agreement between CVD prediction of Iran Package of Essential Non-communicable Disease (IraPEN) and Framingham risk score (FRS). Methods: All 40-79 years old participants in the Yazd Health Study who did not have a history of CVD were included. The 10-years risk of CVD was estimated by the laboratory (IraPEN), non-laboratory WHO-EMR B and FRS. The risk was classified into low, moderate and high-risk groups. Cohen's weighted kappa statistics were used to assess agreement between tools. To assess discrepancies McNemar's χ2 test for paired data was used. P values < 0.05 were considered statistically significant. Results: In total, 2103 participant was included and the risk scores were calculated. Of them, 26.5% were stratified as high risk by FRS, compared with 6.1% by IraPEN. A slight agreement (37.9%) was observed (kappa 0.17, P < 0.0001), in other words. This discrepancy between IraPEN vs. FRS was seen in both sexes (P < 0.0001), although in women the agreement ratio was higher (52.1% vs. 21.3%). The discrepancy between FRS and IraPEN in categorizing people at risk of CVD was 55.5%, (P < 0.0001) but this was not significant between IraPEN and non-laboratory WHO-EMR-B (World Health Organization - Eastern Mediterranean Regional-B group countries) score (P < 0.523; discrepancies, 5.8%). Conclusion: Our study shows a slight agreement between various CVD risk scores. Thus, reviewing the IraPEN and using alternative tools for the low-risk group should be considered by decision-makers. It is important to use a more reliable score for nation-wide risk assessment.


Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome.
The chromosomal protein SMCHD1 plays an important role in epigenetic silencing at diverse loci, including the inactive X chromosome, imprinted genes, and the facioscapulohumeral muscular dystrophy locus. Although homology with canonical SMC family proteins suggests a role in chromosome organization, the mechanisms underlying SMCHD1 function and target site selection remain poorly understood. Here we show that SMCHD1 forms an active GHKL-ATPase homodimer, contrasting with canonical SMC complexes, which exist as tripartite ring structures. Electron microscopy analysis demonstrates that SMCHD1 homodimers structurally resemble prokaryotic condensins. We further show that the principal mechanism for chromatin loading of SMCHD1 involves an LRIF1-mediated interaction with HP1γ at trimethylated histone H3 lysine 9 (H3K9me3)-modified chromatin sites on the chromosome arms. A parallel pathway accounts for chromatin loading at a minority of sites, notably the inactive X chromosome. Together, our results provide key insights into SMCHD1 function and target site selection.


Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13.
To assess the association of ocular disorders and high doses of antioxidants or zinc with mortality in the Age-Related Eye Disease Study (AREDS). Baseline fundus and lens photographs were used to grade the macular and lens status of AREDS participants. Participants were randomly assigned to receive oral supplements of high-dose antioxidants, zinc, antioxidants plus zinc, or placebo. Risk of all-cause and cause-specific mortality was assessed using adjusted Cox proportional hazards models. During median follow-up of 6.5 years, 534 (11%) of 4753 AREDS participants died. In fully adjusted models, participants with advanced age-related macular degeneration (AMD) compared with participants with few, if any, drusen had increased mortality (relative risk [RR], 1.41; 95% confidence interval [CI], 1.08-1.86). Advanced AMD was associated with cardiovascular deaths. Compared with participants having good acuity in both eyes, those with visual acuity worse than 20/40 in 1 eye had increased mortality (RR, 1.36; 95% CI, 1.12-1.65). Nuclear opacity (RR, 1.40; 95% CI, 1.12-1.75) and cataract surgery (RR, 1.55; 95% CI, 1.18-2.05) were associated with increased all-cause mortality and with cancer deaths. Participants randomly assigned to receive zinc had lower mortality than those not taking zinc (RR, 0.73; 95% CI, 0.61-0.89). The decreased survival of AREDS participants with AMD and cataract suggests that these conditions may reflect systemic rather than only local processes. The improved survival in individuals randomly assigned to receive zinc requires further study.


The nuclear hormone receptor PPARγ as a therapeutic target in major diseases.
The peroxisome proliferator-activated receptor γ (PPARγ belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.


Evaluation of the Antioxidant Potency of Seseli L. Species (Apiaceae).
In the present study, the antioxidant potency of ethyl acetate (AcOEt) and methanol (MeOH) extracts from the aerial parts of Seseli L. species was investigated for the first time. Seseli species L. such as Seseli andronakii Woronow ex Schischk., S. campestre Besser, S. corymbosum Boiss. & Heldr., S. gummiferum subsp. gummiferum Pall. ex Sm., S. hartvigii Parolly & Nordt, S. libanotis (L.) W.Koch, S. petraeum M.Bieb., S. peucedanoides (M.Bieb.) Koso-Pol., S. resinosum Freyn & Sint., and S. tortuosum L. growing in Turkey were collected and evaluated for their antioxidant capacity by using 1.1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and lipid peroxidation (LPO) inhibition methods. The highest activities as a scavenger of DPPH radicals were found in the AcOEt extracts of S. peucedanoides (M.Bieb.) Koso-Pol (IC50=0.49 mg/mL), and S. libanotis (IC50=0.75 mg/mL); α-tocopherol was used as a positive control. On the other hand, in the LPO assay, the highest activities were determined in AcOEt and MeOH extracts (at 5 mg/mL) of S. tortuosum and S. libanotis (84-94%). This report gives important information about the antioxidant capacity of Seseli L. species. This research on antioxidant capacity proves that the use of some species used in Eastern Anatolia (in salads) is correct. With this screening study performed in Seseli L. species growing in Turkey, in the future, it is planned to isolate antioxidant compounds from the most active strains of Seseli L.


Geometry shapes evolution of early multicellularity.
Organisms have increased in complexity through a series of major evolutionary transitions, in which formerly autonomous entities become parts of a novel higher-level entity. One intriguing feature of the higher-level entity after some major transitions is a division of reproductive labor among its lower-level units in which reproduction is the sole responsibility of a subset of units. Although it can have clear benefits once established, it is unknown how such reproductive division of labor originates. We consider a recent evolution experiment on the yeast Saccharomyces cerevisiae as a unique platform to address the issue of reproductive differentiation during an evolutionary transition in individuality. In the experiment, independent yeast lineages evolved a multicellular "snowflake-like" cluster formed in response to gravity selection. Shortly after the evolution of clusters, the yeast evolved higher rates of cell death. While cell death enables clusters to split apart and form new groups, it also reduces their performance in the face of gravity selection. To understand the selective value of increased cell death, we create a mathematical model of the cellular arrangement within snowflake yeast clusters. The model reveals that the mechanism of cell death and the geometry of the snowflake interact in complex, evolutionarily important ways. We find that the organization of snowflake yeast imposes powerful limitations on the available space for new cell growth. By dying more frequently, cells in clusters avoid encountering space limitations, and, paradoxically, reach higher numbers. In addition, selection for particular group sizes can explain the increased rate of apoptosis both in terms of total cell number and total numbers of collectives. Thus, by considering the geometry of a primitive multicellular organism we can gain insight into the initial emergence of reproductive division of labor during an evolutionary transition in individuality.


See your ideas in print: write for a professional journal.
Those who have sometimes thought about writing for a professional journal should be encouraged by the fact that most journal writers are the same as journal readers-practitioners and educators who have something of potential value to share with others. There are career-enhancing advantages in journal writing, and there can be a significant amount of personal satisfaction as well. Succeeding at writing and placing a journal article requires the following: selecting an appropriate topic; knowing the publication and its audience and framing the article in the appropriate style; working with the journal editor to create an acceptable manuscript, which includes responding positively to the editor's criticisms and suggestions; and observing all submission requirements and deadlines. One who follows this entire process to its positive conclusion will find that journal writing can be an exacting, demanding, frustrating, and immensely satisfying professional activity.


An intervention to improve sleep for people living with dementia: Reflections on the development and co-production of DREAMS:START (Dementia RElAted Manual for Sleep: STrAtegies for RelaTives).
Many people living with dementia experience sleep disturbances yet there are currently no known effective, safe and acceptable treatments. Working with those affected by dementia to co-produce interventions is increasingly promoted to ensure that approaches are fit for purpose and meet the specific needs of target groups. Our aim here is to outline and reflect upon the co-production of Dementia RElAted Manual for Sleep; STrAtegies for RelaTives (DREAMS:START), an intervention to improve sleep for people living with dementia. Our co-production team brought together experts in the development and testing of manualised interventions in dementia care and cognitive behavioural interventions for sleep disorders, with Alzheimer's Society research network volunteers (ASRNVs) whose lives had been affected by dementia. Here we present the process of intervention development. We worked with (ASRNVs) at each stage of the process bringing together 'experts by training' and 'experts by experience'. (ASRNVs)shared their experiences of sleep disturbances in dementia and how they had managed these difficulties, as well as suggestions for how to overcome barriers to putting the intervention into practice; making (DREAMS:START) more accessible and usable for those in need. In this paper we discuss both the benefits and challenges to this process and what we can learn for future work. Collaborating with 'experts by experience' caring for a relative with sleep difficulties helped us to develop a complex intervention in an accessible and engaging way which we have tested and found to be feasible and acceptable in a randomised controlled trial.


Characterization of L1 retrotransposition with high-throughput dual-luciferase assays.
Recent studies employing genome-wide approaches have provided an unprecedented view of the scope of L1 activities on structural variations in the human genome, and further reinforced the role of L1s as one of the major driving forces behind human genome evolution. The rapid identification of novel L1 elements by these high-throughput approaches demands improved L1 functional assays. However, the existing assays use antibiotic selection markers or fluorescent proteins as reporters; neither is amenable to miniaturization. To increase assay sensitivity and throughput, we have developed a third generation assay by using dual-luciferase reporters, in which firefly luciferase is used as the retrotransposition indicator and Renilla luciferase is encoded on the same or separate plasmid for normalization. This novel assay is highly sensitive and has a broad dynamic range. Quantitative data with high signal-to-noise ratios can be obtained from 24- up to 96-well plates in 2-4 days after transfection. Using the dual-luciferase assays, we have characterized profiles of retrotransposition by various human and mouse L1 elements, and detailed the kinetics of L1 retrotransposition in cultured cells. Its high-throughput and short assay timeframe make it well suited for routine tests as well as large-scale screening efforts.


Protective effect of taurine against alendronate-induced gastric damage in rats.
Alendronate (ALD) causes serious gastrointestinal adverse effects. The aim of this study was to investigate whether taurine (TAU), a semi-essential amino acid and an antioxidant, improves the alendronate-induced gastric injury. Rats were administered 20 mg/kg ALD by gavage for 4 days, either alone or following treatment with TAU (50 mg/kg, i.p.). On the last day of treatment, following drug administration, pylorus ligation was performed and 2 h later, rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation and glutathione (GSH) levels, myeloperoxidase (MPO) activity as well as the histologic appearance of the stomach tissues were determined. Chronic oral administration of ALD induced significant gastric damage, increasing lipid peroxidation, MPO activity and collagen content, as well as decreasing tissue GSH levels. Treatment with TAU prevented the damage and also the changes in biochemical parameters. Findings of the present study suggest that ALD induces oxidative gastric damage by a local irritant effect, and that TAU ameliorates this damage by its antioxidant and/or membrane-stabilizing effects.


Improved detection of Parkinsonian resting tremor with feature engineering and Kalman filtering.
Accurate and reliable detection of tremor onset in Parkinson's disease (PD) is critical to the success of adaptive deep brain stimulation (aDBS) therapy. Here, we investigated the potential use of feature engineering and machine learning methods for more accurate detection of rest tremor in PD. We analyzed the local field potential (LFP) recordings from the subthalamic nucleus region in 12 patients with PD (16 recordings). To explore the optimal biomarkers and the best performing classifier, the performance of state-of-the-art machine learning (ML) algorithms and various features of the subthalamic LFPs were compared. We further used a Kalman filtering technique in feature domain to reduce the false positive rate. The Hjorth complexity showed a higher correlation with tremor, compared to other features in our study. In addition, by optimal selection of a maximum of five features with a sequential feature selection method and using the gradient boosted decision trees as the classifier, the system could achieve an average F1 score of up to 88.7% and a detection lead of 0.52 s. The use of Kalman filtering in feature space significantly improved the specificity by 17.0% (p = 0.002), thereby potentially reducing the unnecessary power dissipation of the conventional DBS system. The use of relevant features combined with Kalman filtering and machine learning improves the accuracy of tremor detection during rest. The proposed method offers a potential solution for efficient on-demand stimulation for PD tremor.


Positive and Unlabeled Multi-Graph Learning.
In this paper, we advance graph classification to handle multi-graph learning for complicated objects, where each object is represented as a bag of graphs and the label is only available to each bag but not individual graphs. In addition, when training classifiers, users are only given a handful of positive bags and many unlabeled bags, and the learning objective is to train models to classify previously unseen graph bags with maximum accuracy. To achieve the goal, we propose a positive and unlabeled multi-graph learning (puMGL) framework to first select informative subgraphs to convert graphs into a feature space. To utilize unlabeled bags for learning, puMGL assigns a confidence weight to each bag and dynamically adjusts its weight value to select "reliable negative bags." A number of representative graphs, selected from positive bags and identified reliable negative graph bags, form a "margin graph pool" which serves as the base for deriving subgraph patterns, training graph classifiers, and further updating the bag weight values. A closed-loop iterative process helps discover optimal subgraphs from positive and unlabeled graph bags for learning. Experimental comparisons demonstrate the performance of puMGL for classifying real-world complicated objects.


Seroprevalence of and Risk Factors for Toxoplasma gondii Infection in Cats in Estonia.
In Estonia, northeastern Europe, Toxoplasma gondii seroprevalence in humans has not declined, in contrast to many other countries. The reasons for this are unknown. Domestic cats are important hosts in the epidemiology of the parasite, but information on local feline T. gondii infections has been lacking. An epidemiological cross-sectional study was conducted to estimate the seroprevalence of T. gondii and the risk factors associated with seropositivity in cats in Estonia. Surplus from blood samples that had been collected for unrelated diagnostic purposes from 306 pet cats and 184 shelter cats were analyzed for anti-T. gondii immunoglobulin G antibodies by using a direct agglutination test. Two questionnaires were designed to reveal relevant risk factors for seropositivity. The overall seroprevalence of T. gondii in cats in Estonia was 60.8%. Older age, outdoor access, hunting, living outside the city in the countryside, and not being a purebred cat were among the risk factors associated with seropositivity. T. gondii is highly prevalent in domestic cats in Estonia. This suggests that the environment has been contaminated with T. gondii. Seropositivity indicates previous oocyst shedding, and most of the cats had outdoor access. The increase in T. gondii seroprevalence with age indicates acquired infections, and most of the risk factors were lifestyle-related. Cat owners could diminish the risk of T. gondii infection and also limit the spread of the parasite by not allowing their cats to roam free.


Intercalative binding of ditercalinium to d(CpGpCpG)2: a theoretical study.
The structure of the complex formed between ditercalinium, 2,2'-[4,4'-bipiperidine-1,1'-bis-(ethane-1,2-diyl)]bis(10-me thoxy-7H- pyrido[4,3-c]carbazolium) tetramethane sulfonate (NSC 366241), and the self-complementary tetranucleotide duplex d(CpGpCpG)2 has been investigated by means of a novel theoretical approach for modelling the conformational flexibility of nucleic acids. The methodology used is the JUMNA procedure, a molecular mechanics systematics capable of evaluating the internal energy and the interaction energy of a complex formed from a large number of fragments. In the best energy-minimized structures, the piperidinium chains of ditercalinium are located in the major groove of the right-handed oligonucleotide. Calculations show a distortion of the base-paired d(CpGpCpG)2 minihelix consisting of lateral dislocation of one base pair with respect to another along an axis parallel to the long axis; strong propeller twist and tilt of the end base pairs; a collective motion of all base pairs with respect to the helical axis towards the drug; and an overwinding at the exclusion site. The proposed structure of the complex is in good agreement with reported proton NMR data, supporting the feasibility of such model.


Utility of serum lactate on differential diagnosis of seizure-like activity: A systematic review and meta-analysis.
Differentiating epileptic seizures from other causes of Transient Loss of Consciousness (TLOC) remains a challenge in the Emergency Department (ED), where it may lead to erroneous administration of anti-epileptic drugs. Although video electroencephalography (EEG) is the gold standard for diagnosing epileptic seizures, it is not widely available in ED settings. Therefore, simple and quick diagnostic techniques for patients with TLOC in ED are needed. We performed a meta-analysis to review relevant literature and determine the efficacy of serum lactate in differentiating epileptic seizures from other causes of TLOC in the ED setting. We performed a literature search of PubMed and Scopus from inception up to April 2022. Randomized trials and observational (prospective or retrospective) studies reporting lactate levels in adults ≤ 3 h after a TLOC episode were included. The primary outcome of interest was the serum lactate level difference between patients with a generalized tonic-clonic seizures (GTCS) and those with other forms of TLOC. Other outcomes were the differences in serum lactate levels among patients with other types of TLOC, such as psychogenic nonepileptic seizures (PNES), syncope, and non-GTCS. Random-effects meta-analysis was performed to compare the mean difference in serum lactate levels among different types of TLOC. The PROSPERO registration is CRD42022316163. We included eight studies (1348 patients) in our analysis. Serum lactate levels from patients who had GTCS were significantly higher than those from patients who had TLOC from any other cause (mean difference 5.27 mmol/L, 95% CI 1.73, 8.81, P = 0.004). Similarly, there was statistically a significant difference in serum lactate between patients with GTCS and non-GTCS (2.96 mmol/L, 95% CI 1.68, 4.24, P = 0.001), and patients with GTCS and syncope (4.29 mmol/L, 95% CI 2.48, 6.10, P = 0.001). However, there was no difference in mean lactate between syncope and PNES, and between syncope and non-GTCS, demonstrating that the serum lactate levels between other forms of TLOC other than GTCS were similar. A serum lactate concentration of 2.4 mmol/L provided a good capability to differentiate between GTCS and non-GTCS, with AUROC ranging from 0.94 - 0.97. Serum lactate can be a valuable tool to differentiate GTCS from other forms of TLOC, but it is not valuable in distinguishing non-GTCS types of TLOC from each other. However, lactate level should not be used as an absolute diagnostic tool and should be interpreted along with proper clinical context.


Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study.
Obesity shortens life expectancy. Bariatric surgery is known to reduce the long-term relative risk of death, but its effect on life expectancy is unclear. We used the Gompertz proportional hazards regression model to compare mortality and life expectancy among patients treated with either bariatric surgery (surgery group) or usual obesity care (control group) in the prospective, controlled Swedish Obese Subjects (SOS) study and participants in the SOS reference study (reference cohort), a random sample from the general population. In total, 2007 and 2040 patients were included in the surgery group and the control group, respectively, and 1135 participants were included in the reference cohort. At the time of the analysis (December 31, 2018), the median duration of follow-up for mortality was 24 years (interquartile range, 22 to 27) in the surgery group and 22 years (interquartile range, 21 to 27) in the control group; data on mortality were available for 99.9% of patients in the study. In the SOS reference cohort, the median duration of follow-up was 20 years (interquartile range, 19 to 21), and data on mortality were available for 100% of participants. In total, 457 patients (22.8%) in the surgery group and 539 patients (26.4%) in the control group died (hazard ratio, 0.77; 95% confidence interval [CI], 0.68 to 0.87; P<0.001). The corresponding hazard ratio was 0.70 (95% CI, 0.57 to 0.85) for death from cardiovascular disease and 0.77 (95% CI, 0.61 to 0.96) for death from cancer. The adjusted median life expectancy in the surgery group was 3.0 years (95% CI, 1.8 to 4.2) longer than in the control group but 5.5 years shorter than in the general population. The 90-day postoperative mortality was 0.2%, and 2.9% of the patients in the surgery group underwent repeat surgery. Among patients with obesity, bariatric surgery was associated with longer life expectancy than usual obesity care. Mortality remained higher in both groups than in the general population. (Funded by the Swedish Research Council and others; SOS ClinicalTrials.gov number, NCT01479452.).


Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines.
Glioblastoma multiforme represents a largely incurable tumor for which novel therapeutic strategies are required. We report the effect of NVP-AEW541, an inhibitor of insulin-like growth factor-I receptor (IGF-IR) kinase activity on growth and signaling in a panel of glioma cell lines. NVP-AEW541 blocked phosphorylation of IGF-IR in a dose- and time-dependent manner and inhibited proliferation and clonogenicity with median effective concentrations of 2.5-10 microM. NVP-AEW541 also induced loss of mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria. Because concentrations of NVP-AEW541 required to significantly inhibit glioma cell viability and downstream signaling also inhibited non-neoplastic astrocytes, we questioned whether differential efficacy could be enhanced by combination with inhibition of other tyrosine kinases dysregulated in gliomas. Dasatinib was selected as a combination agent based on its distinct inhibitory profile for other relevant signaling targets. Combined treatment with NVP-AEW541 and dasatinib induced significantly more apoptosis than either agent alone in glioma cells, but not non-neoplastic astrocytes, and synergistically inhibited clonogenic survival. Mechanistic studies indicated that combination of NVP-AEW541 and dasatinib significantly reduced pERK and pAkt and markedly increased AIF release, Bax oligomerization and loss of mitochondrial potential compared to each agent alone. Overexpression of Bcl-2 and Akt significantly attenuated NVP-AEW541 and dasatinib-induced Bax activation and cell death. Our data indicate that activation of Bax plays a critical role in mediating NVP-AEW541 and dasatinib-induced apoptosis, and suggest the potential value of combining IGFR inhibition with other classes of tyrosine kinase inhibitors to potentiate therapeutic efficacy.


In vivo dose verification from back projection of a transit dose measurement on the central axis of photon beams.
In vivo dose verification is used to prevent major deviations between the prescribed dose and the dose really delivered to the patient. This work presents a quick and simple alternative method for verification of dose delivered to the patient using photon beams. During the treatment session, a transit dose is measured with the EPID and the dose in the patient is estimated from back projection of the portal dose. The formalism for dose calculation is described. It is independent of the detector and has been validated for different beam energies using an ionization chamber (IC). Central axis doses estimated by this formalism were compared with measured dose. Subsequently, the IC was replaced by the EPID appropriately calibrated. The feasibility of the method and its applicability in clinical use has been evaluated on 3 8 patients treated with conformal therapy for various localizations. Ratios between stated and measured doses are reported. They are within the accepted tolerance of classical in vivo dosimetry (SD of 3.5%). The proposed method for in vivo dose verification is very simple to implement and to use in clinics. Measurements can be repeated during several sessions giving the opportunity to built new strategies for the validation by statistical evaluation of the data. The trending of in vivo dose along the treatment becomes also possible. The number of checkable beams is also increased by this method.


Applications in image-based profiling of perturbations.
A dramatic shift has occurred in how biologists use microscopy images. Whether experiments are small-scale or high-throughput, automatically quantifying biological properties in images is now widespread. We see yet another revolution under way: a transition towards using automated image analysis to not only identify phenotypes a biologist specifically seeks to measure ('screening') but also as an unbiased and sensitive tool to capture a wide variety of subtle features of cell (or organism) state ('profiling'). Mapping similarities among samples using image-based (morphological) profiling has tremendous potential to transform drug discovery, functional genomics, and basic biological research. Applications include target identification, lead hopping, library enrichment, functionally annotating genes/alleles, and identifying small molecule modulators of gene activity and disease-specific phenotypes.


The amounts of fluoride in current fluoride therapies: safety considerations for children.
With the increased use of various fluoride preparations for caries prevention, all dental personnel should know their potential toxicity and the margins of safety associated with their use. An understanding of the body's mechanisms for handling fluoride provides a rational basis for assessing the possible risks of excessive fluoride ingestion. Five to 10 grams of sodium fluoride is considered a Certainly Lethal Dose (CLD) for a 70 kg adult. One quarter of the CLD can be ingested without producing serious acute toxicity, and is known as the Safety Tolerated Dose (STD). CLDs and STDs for most commonly used fluoride agents and procedures show that they can be applied with little or no risk of adverse effects, as long as they are handled judiciously. If their use is abused, there is a risk of illness or even death. If amounts of fluoride close to the CLD are ingested, the speed of initiating proper treatment is critical for survival. Vomiting should be induced, if it is not spontaneous; fluoride-binding liquids, such as milk, administered; and the patient taken to the nearest hospital for emergency care. Frequent ingestion of low, but excessive quantities of fluoride during the period of tooth formation can lead to dental fluorosis. Particular concern is warranted for the ingestion of fluoride-containing toothpastes by young children and the inappropriate use of dietary fluoride supplements in communities with sufficient fluoride already present in drinking water. Parents should brush the teeth of preschool children or, at the very least, dispense only small amounts of toothpaste for them (a pea-size portion). Dentists and physicians should know the fluoride concentration of a patient's water supply before prescribing fluoride supplements. Fluoride preparations should be dispensed in appropriate quantities; labeled with suitable cautionary statements; packaged, when appropriate, with childproof closures or in tearproof materials; and stored in safe locations. Practitioners should use only FDA- or ADA- approved products, employ recommended methods for their delivery; know their toxicity; and be familiar with emergency measures for treating accidental overdosages. The risk of adverse effects is small, when fluorides are handled judiciously.


Revealing Missing Human Protein Isoforms Based on Ab Initio Prediction, RNA-seq and Proteomics.
Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.