Stereotactic body radiotherapy for liver tumors: principles and practical guidelines of the DEGRO Working Group on Stereotactic Radiotherapy.
This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a practical guideline for safe and effective stereotactic body radiotherapy (SBRT) of liver tumors. The literature on the clinical evidence of SBRT for both primary liver tumors and liver metastases was reviewed and analyzed focusing on both physical requirements and special biological characteristics. Recommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to critical organs at risk are provided. SBRT is a well-established treatment option for primary and secondary liver tumors associated with low morbidity.


Biomechanical comparison of interfragmentary compression in transverse fractures of the olecranon.
Compression and absolute stability are important in the management of intra-articular fractures. We compared tension band wiring with plate fixation for the treatment of fractures of the olecranon by measuring compression within the fracture. Identical transverse fractures were created in models of the ulna. Tension band wires were applied to ten fractures and ten were fixed with Acumed plates. Compression was measured using a Tekscan force transducer within the fracture gap. Dynamic testing was carried out by reproducing cyclical contraction of the triceps of 20 N and of the brachialis of 10 N. Both methods were tested on each sample. Paired t-tests compared overall compression and compression at the articular side of the fracture. The mean compression for plating was 819 N (sd 602, 95% confidence interval (CI)) and for tension band wiring was 77 N (sd 19, 95% CI) (p = 0.039). The mean compression on the articular side of the fracture for plating was 343 N (sd 276, 95% CI) and for tension band wiring was 1 N (sd 2, 95% CI) (p = 0.038). During simulated movements, the mean compression was reduced in both groups, with tension band wiring at -14 N (sd 7) and for plating -173 N (sd 32). No increase in compression on the articular side was detected in the tension band wiring group. Pre-contoured plates provide significantly greater compression than tension bands in the treatment of transverse fractures of the olecranon, both over the whole fracture and specifically at the articular side of the fracture. In tension band wiring the overall compression was reduced and articular compression remained negligible during simulated contraction of the triceps, challenging the tension band principle.


Food specific oral immunotherapy: a potential treatment for food allergy.
Food allergy is a potentially life-threatening condition affecting up to 8% of children and up to 2% of adults in westernized countries. There are currently no approved treatments for food allergy apart from avoidance. The apparent increase in incidence of food allergies over the past few decades calls attention to the need for effective, disease-modifying therapies for food allergies. Oral immunotherapy (OIT) is a promising experimental treatment in which food allergic patients consume increasing quantities of food in attempt to increase their threshold for allergic reaction. Studies are ongoing to determine whether OIT is capable of safely inducing not only desensitization but also tolerance to the allergenic foods. This article focuses on recent relevant studies of OIT for the treatment of common food allergies.


RNA editing in kinetoplastid protozoa.
Mitochondrial transcripts in kinetoplastids undergo remarkable posttranscriptional editing by uridylate insertion and deletion. The often dramatic remodeling of pre-mRNA sequences is directed by small guide RNAs (gRNAs) to produce mature mRNAs. In vitro analyses of editing have been used to determine the mechanism of editing and show that editing occurs by a series of enzyme-catalyzed steps. They also show that chimeric gRNA/mRNA molecules are not editing intermediates as proposed but are aberrant end products of editing. The complexes and molecules that catalyze editing are now being identified and characterized. The origin of editing, its developmental regulation which helps control the switching between terminal respiratory systems during the life cycle of trypanosomes, and other areas for future study are discussed.


A bump on a bump? Emerging intuitions concerning the relative difficulty of the sciences.
In 4 studies, the authors examined how intuitions about the relative difficulties of the sciences develop. In Study 1, familiar everyday phenomena in physics, chemistry, biology, psychology, and economics were pretested in adults, so as to be equally difficult to explain. When participants in kindergarten, Grades 2, 4, 6, and 8, and college were asked to rate the difficulty of understanding these phenomena, children revealed a strong bias to see natural science phenomena as more difficult than those in psychology. The perceived relative difficulty of economics dropped dramatically in late childhood. In Study 2, children saw neuroscience phenomena as much more difficult than cognitive psychology phenomena, which were seen as more difficult than social psychology phenomena, even though all phenomena were again equated for difficulty in adults. In Study 3, we explored the basis for these results in intuitions about common knowledge and firsthand experience. Study 4 showed that the intuitions about the differences between the disciplines were based on intuitions about difficulty of understanding and not on the basis of more general intuitions about the feasibility or truth of the phenomena in question. Taken together, in the studies, the authors find an early emerging basis for judgments that some sciences are intrinsically more difficult than others, a bias that may persevere in adults in subtler forms in such settings as the courtroom.


Attention, competition, and the parietal lobes: insights from Balint's syndrome.
Simultanagnosia (resulting from occipito-parietal damage) is a profound visual deficit, which impairs the ability to perceive multiple items in a visual display, while preserving the ability to recognise single objects. Here we demonstrate in a patient presenting with Balint's syndrome that this deficit may result from an extreme form of competition between objects which makes it difficult for attention to be disengaged from an object once it has been selected.


Could the CARE-SHAKTI intervention for injecting drug users be maintaining the low HIV prevalence in Dhaka, Bangladesh?
To explore whether the low HIV prevalence observed in Bangladesh results from prevention activities, this study uses mathematical modelling to estimate the impact of a needle/syringe exchange intervention for injecting drug users (IDUs) in Dhaka, Bangladesh. Epidemiological, behavioural and intervention monitoring data were used to parameterize a dynamic mathematical model, and fit it to National HIV Sero-surveillance data among IDUs (2000-02). The model was used to estimate the impact of the intervention on HIV transmission among IDUs and their sexual partners. Dhaka, Bangladesh, where the HIV prevalence has remained low despite high-risk sexual and injecting behaviours, and growing HIV epidemics in neighbouring countries. The model predicts that the intervention may have reduced the incidence of HIV among IDUs by 90% (95% CI 74-94%), resulting in an IDU HIV prevalence of 10% (95% CI 4-19%) after 8 years of intervention activity instead of 42% (95% CI 30-47%) if the intervention had not occurred. The analysis highlights the potential for rapid HIV spread among IDUs in Dhaka, and suggests that the intervention may have substantially reduced IDU HIV transmission. However, there is no room for complacency. Sustained and expanded funding for interventions in Dhaka and other regions of Bangladesh are crucial to maintaining the low HIV prevalence.


Roles of four Arabidopsis U-box E3 ubiquitin ligases in negative regulation of abscisic acid-mediated drought stress responses.
AtPUB18 and AtPUB19 are homologous U-box E3 ubiquitin ligases in Arabidopsis (Arabidopsis thaliana). AtPUB19 is a negative regulator of abscisic acid (ABA)-mediated drought responses, whereas the role of AtPUB18 in drought responses is unknown. Here, loss-of-function and overexpression tests identified AtPUB18 as a negative regulator in ABA-mediated stomatal closure and water stress responses. The atpub18-2atpub19-3 double mutant line displayed more sensitivity to ABA and enhanced drought tolerance than each single mutant plant; therefore, AtPUB18 and AtPUB19 are agonistic. Stomatal closure of the atpub18-2atpub19-3 mutant was hypersensitive to hydrogen peroxide (H(2)O(2)) but not to calcium, suggesting that AtPUB18 and AtPUB19 exert negative effects on the ABA signaling pathway downstream of H(2)O(2) and upstream of calcium. AtPUB22 and AtPUB23 are other U-box E3 negative regulators of drought responses. Although atpub22atpub23 was more tolerant to drought stress relative to wild-type plants, its ABA-mediated stomatal movements were highly similar to those of wild-type plants. The atpub18-2atpub19-3atpub22atpub23 quadruple mutant exhibited enhanced tolerance to drought stress as compared with each atpub18-2atpub19-3 and atpub22atpub23 double mutant progeny; however, its stomatal behavior was almost identical to the atpub18-2atpub19-3 double mutant in the presence of ABA, H(2)O(2), and calcium. Overexpression of AtPUB18 and AtPUB19 in atpub22atpub23 effectively hindered ABA-dependent stomatal closure, but overexpression of AtPUB22 and AtPUB23 in atpub18-2atpub19-3 did not inhibit ABA-enhanced stomatal closure, highlighting their ABA-independent roles. Overall, these results suggest that AtPUB18 has a linked function with AtPUB19, but is independent from AtPUB22 and AtPUB23, in negative regulation of ABA-mediated drought stress responses.


Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.
To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.


Polarization recycling method for light-pipe-based optical engine.
In this paper, a polarization recycling method is proposed for a light-pipe-based liquid crystal on silicon (LCoS) pico-optical engine. The method is based on making use of the virtual light sources array forming at the light pipe's input surface. With traditional imaging optics, the virtual light sources array can be imaged to a plane after the light pipe, where the separated beams array can be obtained. By applying the polarization conversion system to the separated beams, the incoming unpolarized light can be converted to polarized light. The polarized light is then collected and transferred to the LCoS panel through the relay system. This new polarization recycling method can highly improve the light efficiency. A design example of a 0.29 in. (7.366 mm) color-filter LCoS pico-optical engine with 852×480 resolution is listed. High light efficiency of about 10.5 lm per LED Watt and high irradiance uniformity of about 95% has been achieved. The thickness of the optical engine is 8 mm.


Homeostatic control of Argonaute stability by microRNA availability.
Homeostatic mechanisms regulate the abundance of several components in small-RNA pathways. We used Drosophila and mammalian systems to demonstrate a conserved homeostatic system in which the status of miRNA biogenesis controls Argonaute protein stability. Clonal analyses of multiple mutants of core Drosophila miRNA factors revealed that stability of the miRNA effector AGO1 is dependent on miRNA biogenesis. Reciprocally, ectopic transcription of miRNAs within in vivo clones induced accumulation of AGO1, as did genetic interference with the ubiquitin-proteasome system. In mouse cells, we found that the stability of Ago2 declined in Dicer-knockout cells and was rescued by proteasome blockade or introduction of either Dicer plasmid or Dicer-independent miRNA constructs. Notably, Dicer-dependent miRNA constructs generated pre-miRNAs that bound Ago2 but did not rescue Ago2 stability. We conclude that Argonaute levels are finely tuned by cellular availability of mature miRNAs and the ubiquitin-proteasome system.


Automatic deformation analysis by a TV speckle interferometer using a laser diode.
A phase-shifting TV speckle interferometer is developed by using the frequency modulation capability of a laser diode and is applied to automatic deformation measurements. Temperature modulation is used for generating the frequency shift of a laser diode. We store four speckle interferograms with relative phase differences of pi/2 in a frame grabber by monitoring a phase-shift signal, which is obtained by integrating the fringe intensity over a local window. The optimum size of the local window is examined experimentally. Then, the optimum processing conditions for reducing the speckle noise in interferograms,including an averaging window size, are found. Experimental results of the automatic deformation analysis indicate a displacement accuracy of better than lambda/30.


Substrate reduction therapy.
The therapeutic options for lysosomal storage diseases (LSDs) have expanded greatly over the past decade, although for many disorders there is still no effective treatment. Given that the majority of LSDs involve pathological changes in both the brain and peripheral tissues, effective treatment of central nervous system (CNS) and peripheral manifestations still remains a considerable technical challenge. Type 1 Gaucher disease has two approved treatment modalities - enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) - which have unique, independent and potentially complementary mechanisms of action. The availability of these two therapies has greatly increased the options for the effective clinical management of type 1 Gaucher disease. ERT involves the intravenous administration of fully functional enzyme that is taken up by cells and delivered to the lysosome, where it can compensate for the underlying enzyme deficiency. SRT uses an orally available, small molecule drug that inhibits the first committed step in glycosphingolipid biosynthesis. The aim is to reduce the rate of biosynthesis of glycosphingolipids to offset the catabolic defect, restoring the balance between the rate of biosynthesis and the rate of catabolism. SRT also has the potential to treat LSDs with CNS pathology, as the drug in clinical use (miglustat, Zavesca; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) crosses the blood-brain barrier. In this review, the current status of SRT for the treatment of Gaucher disease and other LSDs will be discussed, based upon preclinical and clinical studies. SRT is an oral alternative treatment option for patients with type 1 Gaucher disease unwilling or unable to receive ERT. With the recent reports of clinical improvement/stabilization of CNS manifestations following SRT in patients with Niemann-Pick disease type C, miglustat may also have a role to play in the management of patients with glycosphingolipid storage in the brain. Furthermore, as SRT synergises with other therapeutic modalities, it may also prove to be a key component of combination therapies in the future.


IGF-1 Mediates EphrinB1 Activation in Regulating Tertiary Dentin Formation.
Eph receptors belong to a subfamily of receptor tyrosine kinases that are activated by membrane-spanning ligands called ephrins. Previously, we demonstrated that the ephrinB1-EphB2 interaction regulates odontogenic/osteogenic differentiation from dental pulp cells (DPCs) in vitro. The goal of this study was to identify the molecular mechanisms regulated by the EphB2/ephrinB1 system that govern tertiary dentin formation in vitro and in vivo. During tooth development, ephrinB1, and EphB2 were expressed in preodontoblast and odontoblasts at postnatal day 4. EphrinB1 was continuously expressed in odontoblasts and odontoblastic processes until the completion of tooth eruption. In addition, ephrinB1 was expressed in odontoblastic processes 2 wk following tooth injury without pulp exposure, whereas EphB2 was expressed in the center of pulp niches but not odontoblasts. In a model of tooth injury with pulp exposure, ephrinB1 was strongly expressed in odontoblasts 4 wk postinjury. In vitro studies with human and mouse DPCs treated with calcium hydroxide (CH) or mineral trioxide aggregate (MTA) showed an increased expression of insulin-like growth factor 1 (IGF-1). Experiments using several inhibitors of IGF-1 receptor signaling revealed that inhibiting the Ras/Raf-1/MAPK pathway inhibited EphB2 expression, and inhibiting the PI3K/Akt/mTOR pathway specifically inhibited ephrinB1 gene expression. Tooth injury in mice with odontoblast-specific IGF-1 receptor ablation exhibited a reduced tertiary dentin volume, mineral density, and ephrinB1 expression 4 wk following injury. We conclude that the IGF-1/ephrinB1 axis plays significant roles in the early stages of tooth injury. Further research is needed to fully understand the potential of targeting ephrinB1 as a regenerative pulp therapy.


The development of attitudes about physical punishment: an 8-year longitudinal study.
We examined young adolescents' endorsement of parental use of corporal punishment to elucidate processes underlying the intergenerational transmission of discipline strategies. The community sample was ethnically and socioeconomically diverse. Mothers completed interviews and questionnaires when the target children were entering kindergarten (n = 566) and in 6th and 8th grades. Adolescents completed questionnaires when they were in 8th grade (n = 425). Adolescents' attitudes about corporal punishment varied widely. Those adolescents who had been spanked by their own mothers were more approving of this discipline method, regardless of the overall frequency, timing, or chronicity of physical discipline they had received. However, there was no correlation among adolescents for whom physical maltreatment in early or middle childhood was suspected.


Detection of ultrasound-modulated diffuse photons using spectral-hole burning.
The lack of efficient detection techniques has so far prevented ultrasound-modulated optical tomography from achieving maturity. By applying a quantum spectral filter based on spectral-hole burning, one modulation sideband of the ultrasound-modulated diffuse photons can be efficiently selected while the DC and the other sidebands are blocked. This technique features a large etendue as well as the capability of processing numerous speckles in parallel. It is also immune to speckle decorrelation, potentially allowing real-time in vivo imaging. Both theory and experiments are presented.


Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005.
The treatment of patients with CF has continued to evolve. We hypothesised that sputum microbiology may have changed as a result of this. Retrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database. Colonisation with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p=0.159; 54 to 47%, p=0.108; respectively). Haemophilus influenzae (48 to 6%; p<0.001), Aspergillus species (18 to 9%; p=0.002) and Burkholderia cepacia complex (9 to 4%; p=0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p=0.02; 1 to 6%, p=0.002, respectively). P. aeruginosa colonisation has remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.


Placebo expectancy effects in the relationship between glucose and cognition.
The present study investigated the extent of expectancy in the ability of glucose to affect cognitive performance. Using a within-subjects design, subjects (n 26) completed four experimental sessions (in counterbalanced order and after an initial practice session) during which they were given a 500 ml drink 30 min prior to completing a cognitive assessment battery. In addition, all subjects completed a baseline practice session during which they were given no drink. During two of the sessions, subjects were given a drink containing 50 g glucose and on the other two they were given a drink containing aspartame. A balanced placebo design was used, such that for half the sessions subjects were accurately informed as to the content of the drink (glucose or aspartame), whereas in the other two sessions they were misinformed as to the content of the drink. The task battery comprised a 6 min visual analogue of the Bakan vigilance task, an immediate verbal free-recall task, an immediate verbal recognition memory task and a measure of motor speed (two-finger tapping). Blood glucose and self-reported mood were also recorded at several time points during each session. Glucose administration was found to improve recognition memory times, in direct contrast to previous findings in the literature. Glucose administration also improved performance on the Bakan task (relative to the control drink), but only in sessions where subjects were informed that they would receive glucose and not when they were told that they would receive aspartame. There were no effects either of the nature of the drink or expectancy on the other measures. These results are interpreted in terms of there being some contribution of expectancy concerning the positive effects of glucose on cognition in studies which have not used an equi-sweet dose of aspartame as a control drink.


Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.
The classic model of tumor suppression implies that malignant transformation requires full "two-hit" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a "continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor suppression.


Methanol oxidation on stoichiometric and oxygen-rich RuO2(110).
We used temperature-programmed reaction spectroscopy (TPRS) to investigate the adsorption and oxidation of methanol on stoichiometric and O-rich RuO2(110) surfaces. We find that the complete oxidation of CH3OH is strongly preferred on stoichiometric RuO2(110) during TPRS for initial CH3OH coverages below ∼0.33 ML (monolayer), and that partial oxidation to mainly CH2O becomes increasingly favored with increasing CH3OH coverage from 0.33 to 1.0 ML. We present evidence that an adsorbed CH2O2 species serves as the key intermediate to complete oxidation and that CH2O2 formation is intrinsically facile but becomes limited by the availability of bridging O-atoms on stoichiometric RuO2(110) at initial CH3OH coverages above 0.33 ML. We show that methanol molecules adsorbed in excess of 0.33 ML dehydrogenate to mainly CH2O and desorb during TPRS, with adsorbed CH3O groups mediating the evolution of both CH2O and CH3OH. We find that O-rich RuO2(110) surfaces are also highly active toward methanol oxidation and that selectivity toward the complete oxidation of methanol increases markedly with increasing coverage of on-top O-atoms (Oot) on RuO2(110). Our results demonstrate that CH3OH species adsorbed within Oot-rich domains react efficiently during TPRS, in parallel with reaction of CH3OH adsorbed initially on cus-Ru sites. The data suggests that the facile hydrogenation of Oot atoms and the resulting desorption of H2O at low-temperature (<∼400 K) provides an efficient pathway for restoring reactive O-atoms and thereby promoting complete oxidation of methanol on the O-rich RuO2(110) surface.


Mesophilic and Thermophilic Cultures Used in Traditional Cheesemaking.
Most cheese varieties require acidification of milk by a select group of bacteria called starters. They ferment lactose to lactic acid and in so doing aid the cheesemaker in developing the desired texture as well as acidity of the cheese. However, while other microorganisms play the major role in flavor development of cheese, it is the starter that sets the stage for quality cheese manufacture. Starters were traditionally derived from the native microflora of the milk, but this practice is almost unheard of today. With the advent of better hygienic milking practices and industrialized cheesemaking, there was a need for more uniformity and reliable sources of the starter culture. Today's starters are produced by companies specializing in their production as well as in the development of new strains for cheesemakers. The choice of starter for the manufacture of a specific cheese is dictated by the cheesemaking protocol, but it is also governed by the need to produce cheese with desired physical attributes. The properties of the starter that make it possible to do so help drive innovation in developing new potential choices in starter cultures. Indeed, the demands for predictable and reliable rates and extent of acidification of milk for cheesemaking and flavor development are as key for successful cheesemaking today with artisanal cheesemakers as they are for larger, more industrial-scale cheesemakers.


Rhabdomyosarcoma: current challenges and their implications for developing therapies.
Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.


Endoscope-Assisted Transoral Fixation of Mandibular Condyle Fractures: Submandibular Versus Transoral Endoscopic Approach.
In recent years, endoscope-assisted transoral approach for condylar fracture treatment has attracted much attention. However, the surgical approach is technically challenging: the procedure requires specialized instruments and the surgeons experience a steep learning curve. During the transoral endoscopic (TE) approach several instruments are positioned through a narrow oral incision making endoscope maneuvering very difficult. For this reason, the authors changed the entry port of the endoscope from transoral to submandibular area through a small stab incision. The aim of this study is to assess the advantage of using the submandibular endoscopic intraoral approach (SEI).The SEI approach requires intraoral incision for fracture reduction and fixation, and 4 mm size submandibular stab incision for endoscope and traction wires. Fifteen patients with condyle neck and subcondyle fractures were operated under the submandibular approach and 15 patients with the same diagnosis were operated under the standard TE approach.The SEI approach allowed clear visualization of the posterior margin of the ramus and condyle, and the visual axis was parallel to the condyle ramus unit. The TE approach clearly shows the anterior margin of the condyle and the sigmoid notch. The surgical time of the SEI group was 128 minutes and the TE group was 120 minutes (P >0.05). All patients in the TE endoscope group were fixated with the trocar system, but only 2 lower neck fracture patients in the SEI group required a trocar. The other 13 subcondyle fractures were fixated with an angulated screw driver (P <0.05). There were no differences in complication and surgical outcomes.The submandibular endoscopic approach has an advantage of having more space with good visualization, and facilitated the use of an angulated screw driver.


Psychosocial background in incarcerated adolescents from Austria, Turkey and former Yugoslavia.
Adolescents with a migration background account for a substantial proportion of juveniles in custody. Psychosocial adversities pose a significant risk for criminal behaviour. So far, the nature of psychosocial adversities experienced by migrant youth is understudied. The aim of this study was to explore differences in psychosocial background in three ethnic groups (Turkish, former-Yugoslavian and Austrian) of detained juveniles in Austria. A semi-structured interview (Multidimensional Clinical Screening Inventory for delinquent juveniles, MCSI) was used to assess psychosocial background (e.g., trauma, family background, forensic and psychiatric family history, school history, psychiatric treatment received and criminal history) in juveniles entering an Austrian pre-trial detention facility. Of the 370 eligible participants, the final study sample consisted of 278 juveniles. The ethnic distribution was as follows: 55.4% Austrian (mean age 16.88 years, S.D.=1.52), 14% Turkish (mean age 16.28 years, S.D.=1.23), 30.6% former-Yugoslavian (mean age 16.47 years, S.D.=1.41). In the Austrian sample, family dysfunction was significantly more prevalent than in the Turkish or former-Yugoslavian samples. Mental health services were significantly less used by juveniles with migration background. Turkish juveniles had a significantly poorer school performance than Austrians. Juveniles from former-Yugoslavia had significantly less often attended schools offering secondary education. The results suggest that detained juveniles with migration background are poorly integrated into the educational and mental health system of the host society. Family systems, even if substantially dysfunctional, seem to be perceived as more stable by migrant youth than by Austrian youth.


Plasmodium falciparum expressing domain cassette 5 type PfEMP1 (DC5-PfEMP1) bind PECAM1.
Members of the Plasmodium falciparum Erythrocyte Membrane protein 1 (PfEMP1) family expressed on the surface of malaria-infected erythrocytes mediate binding of the parasite to different receptors on the vascular lining. This process drives pathologies, and severe childhood malaria has been associated with the expression of particular subsets of PfEMP1 molecules. PfEMP1 are grouped into subtypes based on upstream sequences and the presence of semi-conserved PfEMP1 domain compositions named domain cassettes (DCs). Earlier studies have indicated that DC5-containing PfEMP1 (DC5-PfEMP1) are more likely to be expressed in children with severe malaria disease than in children with uncomplicated malaria, but these PfEMP1 subtypes only dominate in a relatively small proportion of the children with severe disease. In this study, we have characterised the genomic sequence characteristic for DC5, and show that two genetically different parasite lines expressing DC5-PfEMP1 bind PECAM1, and that anti-DC5-specific antibodies inhibit binding of DC5-PfEMP1-expressing parasites to transformed human bone marrow endothelial cells (TrHBMEC). We also show that antibodies against each of the four domains characteristic for DC5 react with native PfEMP1 expressed on the surface of infected erythrocytes, and that some of these antibodies are cross-reactive between the two DC5-containing PfEMP1 molecules tested. Finally, we confirm that anti-DC5 antibodies are acquired early in life by individuals living in malaria endemic areas, that individuals having high levels of these antibodies are less likely to develop febrile malaria episodes and that the antibody levels correlate positively with hemoglobin levels.


An Examination of Early Maladaptive Schemas among Substance Use Treatment Seekers and their Parents.
Early maladaptive schemas, which are cognitive and behavioral patterns of viewing oneself and the world that result in substantial distress, are gradually being documented as important vulnerabilities for substance abuse. Unfortunately, there is limited research on early maladaptive schemas among substance abusers and their family members. Research on this topic may carry important implications for family-focused substance use interventions. The current study examined similarities and differences in early maladaptive schemas among a sample of substance abuse treatment seeking adults (n = 47) and at least one parent (n = 58). Results demonstrated that the substance abusers scored higher than their parents on 17 of 18 early maladaptive schemas, with most differences falling into the large effect size range. There were some similarities in the specific early maladaptive schemas endorsed by both groups despite substance abusers scoring higher on all schemas. Implications of these findings for future research and family-focused substance use treatment programs are discussed.


Reversibility and energetics in optical computing.
Computer operations that conserve energy do not, from an information viewpoint, increase entropy and therefore have no minimum energy cost associated with them. An information-conserving operation must be reversible in principle; reversible optical gates inevitably incur losses. The energy per calculation may have many meanings, as we show. The energy expended by a single photon in a conservative optical operation is negligible, much less than kT.


Remnant Effects of Culture Density on Cell Chirality After Reseeding.
Proper muscle function requires specific orientation of myotubes. Cell chirality, a mechanical behavior of cells, may participate in myogenesis and give rise to left-right (LR) orientation of muscle tissue. Thus, it is essential to understand the factors effecting the cell chirality. Here, using C2C12 cells as a model system, we report that prior culture condition with high/low density can create remnant effects on cell chirality after reseeding. C2C12 myoblasts were first conditioned by a series of subcultures with plating density at 2200 cells/cm2 (low density) or 22 000 cells/cm2 (high density). After reseeding on micropatterned stripes fabricated on glass or polydimethylsiloxane (PDMS) substrates, we found that the cells after low-density cultures exhibited a reduced cell aspect ratio and intercellular alignment, leading to an attenuated chiral orientation only appearing on glass substrate. In contrast, chiral orientation was observed in cells after high-density culture on both substrates. By comparing it to the original cells without being subcultured with high/low density, we found that the series of low-density cultures disorganized the formation of actin rings in single cells, which is an essential structure for cell chirality. Moreover, by using high-density culture supplemented with inhibitors of actin polymerization, the effect of low-density cultures was recaptured, suggesting that the series of subcultures with high/low density may be an in vitro aging process that modifies the actin cytoskeleton, causing a remnant attenuation of cell chirality even after trypsin digestion and reseeding. Together, our result suggests a mechanistic insight of how cytoskeletal structures "memorize" the previous experience through modification of the actin filament, opening up new possibilities for morphogenesis and mechanobiology.


Biomarker-based methods for determining noncompliance in a prevention trial.
The Prostate Cancer Prevention Trial (PCPT) is a 7-year randomized trial of 18000 men designed to test a daily dose of finasteride (5 mg/d) for the primary prevention of prostate cancer. Compliance is assessed every 6 months by determining the percentage of pills consumed since the previous visit. In addition, levels of 5 alpha-dihydrotestosterone (DHT) are measured at yearly intervals in a random subset of 5% of participants in the trial as part of a substudy to investigate the potential of this biomarker for monitoring compliance. Motivated by this substudy, we outline three biomarker-based rules for monitoring compliance over time in prevention trials. We make comparisons among the rules using receiver operating characteristic curves. We illustrate the methods using the biomarker DHT in the PCPT substudy with pill counts as a gold standard, and in a simulation study under a hypothetical true gold standard. Our results indicate that simple absolute threshold monitoring rules perform just as well as more complicated rules that utilize the entire biomarker history.


Potentiation increases peak twitch torque by enhancing rates of torque development and relaxation.
The aim of this study was to measure the extent to which potentiation changes in response to an isometric maximal voluntary contraction. Eleven physically active subjects participated in two separate studies. Single stimulus of electrical stimulation of the femoral nerve was used to measure torque at rest in unpotentiated quadriceps muscles (study 1 and 2), and potentiated quadriceps muscles torque in a 10 min period after a 5 s isometric maximal voluntary contraction of the quadriceps muscles (study 1). Additionally, potentiated quadriceps muscles torque was measured every min after a further 10 maximal voluntary contractions repeated every min (study 2). Electrical stimulation repeated several times without previous maximal voluntary contraction showed similar peak twitch torque. Peak twitch torque 4 s after a 5 s maximal voluntary contraction increased by 45±13% (study 1) and by 56±10% (study 2), the rate of torque development by 53±13% and 82±29%, and the rate of relaxation by 50±17% and 59±22%, respectively, but potentiation was lost already two min after a 5 s maximal voluntary contraction. There was a tendency for peak twitch torque to increase for the first five repeated maximal voluntary contractions, suggesting increased potentiation with additional maximal voluntary contractions. Correlations for peak twitch torque vs the rate of torque development and for the rate of relaxation were r(2)= 0.94 and r(2)=0.97. The correlation between peak twitch torque, the rate of torque development and the rate of relaxation suggests that potentiation is due to instantaneous changes in skeletal muscle contractility and relaxation.


L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.
L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in L-selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with L-selectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.


Toward a Robust Multi-Objective Metaheuristic for Solving the Relay Node Placement Problem in Wireless Sensor Networks.
During the last decade, Wireless sensor networks (WSNs) have attracted interest due to the excellent monitoring capabilities offered. However, WSNs present shortcomings, such as energy cost and reliability, which hinder real-world applications. As a solution, Relay Node (RN) deployment strategies could help to improve WSNs. This fact is known as the Relay Node Placement Problem (RNPP), which is an NP-hard optimization problem. This paper proposes to address two Multi-Objective (MO) formulations of the RNPP. The first one optimizes average energy cost and average sensitivity area. The second one optimizes the two previous objectives and network reliability. The authors propose to solve the two problems through a wide range of MO metaheuristics from the three main groups in the field: evolutionary algorithms, swarm intelligence algorithms, and trajectory algorithms. These algorithms are the Non-dominated Sorting Genetic Algorithm II (NSGA-II), Strength Pareto Evolutionary Algorithm 2 (SPEA2), Multi-Objective Evolutionary Algorithm based on Decomposition (MOEA/D), Multi-Objective Artificial Bee Colony (MO-ABC), Multi-Objective Firefly Algorithm (MO-FA), Multi-Objective Gravitational Search Algorithm (MO-GSA), and Multi-Objective Variable Neighbourhood Search Algorithm (MO-VNS). The results obtained are statistically analysed to determine if there is a robust metaheuristic to be recommended for solving the RNPP independently of the number of objectives.


Criterion validity of the Motor Coordination and Dexterity Assessment: MCDA for 7- and 8-years old children.
Developmental Coordination Disorder (DCD) is characterized by impaired development of motor coordination, with impact on daily life activities and academic performance. The Motor Coordination and Dexterity Assessment (MCDA) was created to offer Brazilian rehabilitation professionals a valid and reliable instrument for detecting DCD. To examine the MCDA criterion validity. One hundred and eighty one children aged 7 and 8 years from the metropolitan region of Belo Horizonte, MG, Brazil, pre-selected using the Developmental Coordination Disorder Questionnaire (DCDQ-Brazil), were evaluated with the MCDA and the Movement Assessment Battery for Children (MABC-II). Concurrent validity was assessed using Spearman correlation index and the predictive validity was calculated using sensitivity, specificity, positive and negative predictive values. ROC curves were constructed to determine the optimal cutoff point of MCDA. Spearman correlation between the total scores of MCDA and MABC-II at 7 and 8 years were 0.596 (p=0.000) and 0.730 (p=0.000), respectively. The cutoff points defined by the ROC curves approached the 40th percentile, corresponding to a sensitivity of 0.91 and 0.74 and specificity of 0.74 and 0.90 for children 7 and 8 years old, respectively. The results indicate moderate values of concurrent and predictive validity of the MCDA. Future studies should reexamine the cutoff points of the MCDA in other random samples, representative of Brazilian children 4 to 8 years of age. The predictive validity of the full instrument for DCD should be re-examined in well defined clinical samples.


Pomalidomide is effective for prevention and treatment of experimental skin fibrosis.
Tissue fibrosis is a major hallmark and a leading cause of death in systemic sclerosis (SSc). Here, we investigated the antifibrotic effects of pomalidomide, an analogue of thalidomide with potent immunomodulatory effects, in preclinical models of skin fibrosis. We evaluated the antifibrotic effects of pomalidomide in preventive as well as therapeutic treatment regimes using bleomycin-induced dermal fibrosis as a model of early, inflammatory stages of fibrosis and the tight-skin mouse model as a model of later stages of fibrosis with endogenous activation of fibroblasts. Treatment with pomalidomide in doses from 0.3 to 30 mg/kd/day prevented skin fibrosis in Tsk-1 mice and in bleomycin-induced dermal fibrosis in a dose-dependent manner and reduced the expression of transforming growth factor (TGF) β-target genes such as PAI-1, CTGF and col 1a1. Pomalidomide was also effective in the setting of pre-established fibrosis and reduced dermal thickness, myofibroblast counts and hydroxyproline content below pretreatment levels. We demonstrate for the first time that pomalidomide exerts potent antifibrotic effects in different preclinical models of skin fibrosis. These findings lend preclinical support for the clinical studies of pomalidomide in SSc.


Patient-Reported Needs Following a Referral for Colorectal Cancer Screening.
Patient-physician communication about colorectal cancer screening can affect screening use, but discussions often lack information that patients need for informed decision making and seldom address personal preferences or barriers. To address this gap, a series of patient focus groups was conducted to guide the development of an online, interactive decision support program. This article presents findings on patient information needs and barriers to colorectal cancer screening after receiving a screening recommendation from a physician, and their perspectives on using electronic patient portals as platforms for health-related decision support. Primary care patients with recent colonoscopy or stool testing orders were identified via the centralized data repository of a large Midwestern health system. Seven gender-stratified focus groups (N=45 participants) were convened between April and July 2016. Sessions were audio recorded, transcribed, coded, and analyzed for commonly expressed themes beginning in August 2016. Findings reveal a consistent need for simple and clear information on colorectal cancer screening. Participants desired step-by-step explanations of the colonoscopy procedure and information about bowel preparation options/alternatives. The desired level of additional information varied: some patients wanted to know about and act on test options, whereas others preferred following their physician-recommended testing path. Fears and concerns were prevalent, particularly about colonoscopy, and patients reported challenges getting these concerns and their informational needs addressed. Finally, they expressed consistent support for using the patient portal to gather additional information from their physician. Patient portals may offer an opportunity to build sustainable programs for decision support and assistance that are integrated with clinic workflows and processes.


[Identification of a de novo MAP2K1 gene variant in an affected patient with Cardio-facio-cutaneous syndrome].
To explore the genotype-phenotype correlation of Cardio-facio-cutaneous syndrome (CFCS) caused by MAP2K1 gene variants. Genomic DNA was extracted from peripheral blood sample from a child patient and his parents. Whole exome sequencing (WES) was carried out for the patient. Suspected variant was verified by Sanger sequencing. The patient was a 1-year-8-month old Chinese male who manifested short stature, psychomotor retardation, relative macrocephaly, distinctive facial features, and congenital heart disease. WES test revealed a heterozygous missense c.389A>G (p.Tyr130Cys) variant in the MAP2K1 gene. Sanger sequencing has confirmed the variant as de novo. According to ACMG/AMP guidelines, the variant was classified as pathogenic. Compared with previously reported CFCS cases due to MAP2K1 variants. The patient showed obvious behavioral problems, good appetite and tricuspid regurgitation, which may to be novel features for CFCS.


Virtual reconstruction of the Early Pleistocene mandible ATD6-96 from Gran Dolina-TD6-2 (Sierra De Atapuerca, Spain).
In this report, we present a further study of the late Early Pleistocene ATD6-96 human mandible, recovered from the TD6-2 level of the Gran Dolina cave site (Sierra de Atapuerca, northern Spain) and attributed to Homo antecessor. ATD6-96 consists of a left half of a gracile mandible of an adult individual with the premolars and molars in place that is broken at the level of the lateral incisor-canine septum. The present analysis is based on a virtual reconstruction of the whole mandible by means of computed tomography (CT). We have reconstructed the symphysis using information from a modern human sample, as well as from a wide sample composed of several Homo specimens. This research has allowed us to record new variables with taxonomic and phylogenetic interest. We have estimated the length/width index of the alveolar arcade, as well as the percentage of the arcade length with regard to the total length. The latter confirms that ATD6-96 shares with all African and Asian Homo species a primitive structural pattern, as it was established in previous studies. In constrast, the length/width index of the alveolar arcade in the H. antecessor specimen is close to the mean values of Neandertals and the Atapuerca-Sima de los Huesos hominins. H. antecessor is derived regarding the shape of the mandibular alveolar arcade within the genus Homo and points to an early divergence from contemporaneous African populations. Our results also ratify the affinities of H. antecessor with Neanderthals, although the precise relationship with this lineage needs further research.


Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan.
Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival. We performed a prospective, dose-escalation phase Ib study of the topoisomerase-I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas. Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials.


Ethics in scientific communication: study of a problem case.
The hypothermia experiments performed on humans during the Second World War at the German concentration camp in Dachau have been regarded as crimes against humanity, disguised as medical research. For almost 50 years, scientists maintained that the study produced valuable, even if not totally reliable, information. In recent years, the results from the Dachau hypothermia project were glamorized with life-saving potential and a heated ethical dialogue was activated about the use of life-saving but tainted scientific information. In the wake of the debate, an in-depth examination of the scientific rigour of the project was performed and revealed that neither the science nor the scientists from Dachau could be trusted and that the data were worthless. The body of medical opinion accepted the unfavourable determination but a few scientists and ethicists have continued to endorse the validity, of at least parts, of the Dachau hypothermia data. The conduct of the scientific communications about the Dachau hypothermia experiments by the scientific and ethical communities invites serious consideration of a possible ethical misadventure. It appears that for almost 50 years, the results of the study had been endorsed without careful examination of the scientific base of the experiments and that secondary citation of relevant original material may have been commonly employed. These infractions contributed to a myth that good science was practised by the Nazis at Dachau. The more recent emphasis on the life-saving potential of the Dachau data, without citation of credible supporting evidence, has also been misleading. Similarly, acceptance of a determination by an in-depth examination that the 'whole' Dachau project if flawed with simultaneous endorsement of the validity of 'parts' of the results, poses an ethical problem. It is advisable that before seeking ethical consultation about the use of unethically obtained data, scientists should examine the quality of science behind the controversial information and ethicists should verify the integrity of the material prior to engaging in a dialogue.


Using thyroid hormone in brain-dead donors to maximize the number of organs available for transplantation.
The aggressive management of brain-dead (cadaveric) organ donors has been shown to increase organs available for transplantation. Some centers use hormone therapy with thyroid hormone (T(4)) in selected donors. The purpose of this study is to evaluate the effects of T(4) on organs available for transplantation. A policy of aggressive donor management was adopted at our trauma center in 1998. T(4) therapy is reserved for the hemodynamically unstable donors who require significant vasopressor support. The records of patients who successfully donated organs between January 2001 and December 2005 were reviewed. Organ donor demographics and whether T(4) was used was examined for each donor. T(4) was used in 96 of 123 donors (78%). Compared with donors who did not receive T(4), those that did were similar in age (32 +/- 14 vs. 38 +/- 21, p = 0.148), had more organs donated (3.9 +/- 1.7 vs. 3.2 +/- 1.7, p = 0.048), and had no differences in brain-death related complications. Despite the severe hemodynamic instability in the T(4) group, the number of organs harvested from this group was significantly more than in patients who did not receive T(4). The use of T(4) in this group may result in the increased salvage of transplantable organs.


Impact of robotic learning curve on histopathology in rectal cancer: A pooled analysis.
A beneficial impact of robotic proctectomy on circumferential resection margin (CRM) is expected due to the robot's articulating instruments in the pelvis. There are however concerns about a negative impact on the quality of total mesorectal excision (TME) due to the lack of tactile feedback. The aim of this study was to assess whether surgeons' learning curve impacted CRM and TME quality. In a multicenter study, individual patient data of robotic proctectomy for resectable rectal cancer were pooled. Patients were stratified into two phases of surgeons' learning curve. Cumulative sum (CUSUM) analysis was used to determine the transition from learning phase (LP) to plateau phase (PP), which were compared. CRM was microscopically measured in mm by pathologists. TME quality was classified by pathologists as complete, nearly complete or incomplete. T-test and Chi-squared tests were used to compare continuous and categorical variables, respectively. 235 patients underwent robotic proctectomy by five surgeons. 83 LP patients were comparable to 152 PP patients for age (p = 0.20), gender (67.5% vs. 65.1% males; p = 0.72), BMI (p = 0.82), cancer stage (p = 0.36), neoadjuvant chemoradiation (p = 0.13), distance of tumor from anal verge (5.8 ± 4.4 vs. 5.5 ± 3.3; p = 0.56). CRM did not differ (7.7 ± 11.4 mm vs. 8.4 ± 10.3 mm; p = 0.62). The rate of complete TME quality was significantly improved in PP patients as compared to LP patients (73.5% vs. 92.1%; p < 0.001). While learning had no impact on circumferential resection margins, the quality of TME significantly improved during surgeons' plateau phase as compared to their learning phase.


Segmentation of cell clumps for quantitative analysis.
The increasing amounts of microscopy data generated in cell biology requires the development of automated tools for the quantitative analysis of images. Clumps of cells are difficult to segment due to the frequent lack of clear boundaries between cells and are often ignored, but communication between cells is an intrinsic part of the response of cells to their environment. In addition cells often show a large variation in their responses, even within a clump, and an accurate segmentation is therefore vital to prevent the unwanted averaging of measurements over multiple cells. Here we present a method for segmenting clumps of cells by using a multi-scale ridge filter to enhance unclear boundaries. A multi-phase level set method incorporating a region competition term is used to identify a boundary for each cell based on the ridge filter response.


Budget impact analysis of high-flow nasal cannula for infant bronchiolitis: the Colombian National Health System perspective.
High-flow nasal cannula is a non-invasive ventilation system that was introduced as an alternative to continuous positive airway pressure), with a marked increase in its use in pediatric care settings. However, the expected budget impact of this intervention has not been explicitly estimated. This study aimed to evaluate the budget impact of the high-flow nasal cannula for acute bronchiolitis in Colombia. A budget impact analysis was performed to evaluate the potential financial impact deriving from high-flow nasal cannula during 2020. The analysis considered a 5-year time horizon and Colombian National Health System perspective. The incremental budget impact was calculated by subtracting the cost of the new treatment, in which a high-flow nasal cannula is reimbursed, from the cost of the conventional treatment without a high-flow nasal cannula (supplemental oxygen through a nasal cannula up to a maximum of 2 liters per minute). Univariate one-way sensitivity analyses were performed. In the base-case analysis the 5-year costs associated with high-flow nasal cannula and no- high-flow nasal cannula were estimated to be US$159,585,618 and US$172,751,689 respectively, indicating savings for Colombian National Health equal to US$13,166,071 if the high-flow nasal cannula is adopted for the routine management of patients with acute bronchiolitis. This result was robust in univariate sensitivity one-way analysis. High-flow nasal cannula was cost-saving in emergency settings for treating infants with acute bronchiolitis. This evidence can be used by decision-makers in our country to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.


Increased immunoreactive endothelin-1 in human transplant coronary artery disease.
The pathogenesis of transplant coronary artery disease (TCAD) is unknown, but it is thought to derive from an interaction between immune and nonimmune factors, leading to smooth muscle cell proliferation and accumulation in the expanded neointima. Endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties for vascular smooth muscle cells, has recently been demonstrated in native vessel atherosclerosis. The present study used immunohistochemistry to investigate the role of ET-1 in TCAD. ET-1 immunoreactivity and cellular localization were assessed in human coronary arteries with TCAD (n = 13) and in normal coronary arteries (n = 10) with single- and double-label immunohistochemistry. The intensity of immunostaining was determined by a semiquantitative method. Diffuse and intense ET-1 immunoreactivity was found in 11 of 13 patients with TCAD (85%), mainly in myointimal cells and, in lesser amounts, in macrophages and endothelial cells. In contrast, normal coronary arteries had only faint immunostaining localized to the endothelial layer. Mean semiquantitative grade was significantly higher in TCAD than in normal arteries (1.8 versus 0.7; P < .05). ET-1 was more frequently present in lipid-rich, atheromatous lesions than in lipid-poor, proliferative ones. Intimal neovessels consistently immunostained for ET-1. Immunoreactivity for ET-1 is significantly increased in TCAD, possibly as a result of stimulatory cytokines and growth factors that are upregulated in the posttransplant state. The results suggest a role for this mitogenic peptide in the pathogenesis of graft arteriosclerosis.


Use of Google Street View to Assess Environmental Contributions to Pedestrian Injury.
To demonstrate an information technology-based approach to assess characteristics of streets and intersections associated with injuries that is less costly and time-consuming than location-based studies of pedestrian injury. We used imagery captured by Google Street View from 2007 to 2011 to assess 9 characteristics of 532 intersections within New York City. We controlled for estimated pedestrian count and estimated the relation between intersections' characteristics and frequency of injurious collisions. The count of pedestrian injuries at intersections was associated with the presence of marked crosswalks (80% increase; 95% confidence interval [CI] = 2%, 218%), pedestrian signals (156% increase; 95% CI = 69%, 259%), nearby billboards (42% increase; 95% CI = 7%, 90%), and bus stops (120% increase; 95% CI = 51%, 220%). Injury incidence per pedestrian was lower at intersections with higher estimated pedestrian volumes. Consistent with in-person study observations, the information-technology approach found traffic islands, visual advertising, bus stops, and crosswalk infrastructures to be associated with elevated counts of pedestrian injury in New York City. Virtual site visits for pedestrian injury control studies are a viable and informative methodology.


Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinoma.
Epithelial-mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metastasis of various cancers. The aim was to evaluate that whether EMT-related proteins' alterations are associated with clinicopathological features and prognosis in lung adenocarcinoma. The expression of EMT-related proteins including cytokeratin, E-cadherin, TTF-1, β-catenin, vimentin, Snail, Twist, CD44 was evaluated by immunohistochemistry using a tissue array method in the lung adenocarcinoma tissues of 95 patients. In addition, clinicopathological characteristics and survival were compared with the expression of EMT-related proteins. Loss of epithelial proteins and/or acquisition of the expression of mesenchymal proteins were observed in lung adenocarcinoma. These proteins' alteration was associated with poor cell differentiation and poor patients' outcome, respectively. Subjects were divided into two groups according to the number of EMT-related proteins' alteration. A higher number of EMT-related proteins' alteration was found to be significantly associated with unfavorable outcome. Multivariate analysis showed that a higher number of EMT-related proteins' alteration was independently associated with poor prognosis. The number of EMT-related proteins' alteration is a significant prognostic marker to predict overall survival in patients with lung adenocarcinoma. The information generated will be valuable for the prognosis of patients with lung adenocarcinoma. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1007838329872974.


Association of Physical Performance and Fear-Avoidance Beliefs in Adults with Chronic Low Back Pain.
Low back pain is a commonest musculoskeletal disorder affecting majority of people. Activity limitations are difficulties an individual may have in executing activities resulting from person's functioning and disability. According to the fear-avoidance model of low back pain, individuals who perceive pain as a sign of potential damage are more likely to avoid behaviors that increase their anxiety and show sub-maximal performance during physical activity. Purpose of this study was to find the association between activity limitation and fear avoidance belief in patients with chronic low back pain. Thirty subjects with chronic low back pain were included in the study. Activity limitation was measured using Back Performance Scale (BPS). Patients' fear of pain and avoidance of physical activities was assessed with Fear Avoidance Belief Questionnaire (FABQ). It was observed that performance was affected in roll up, fingertip to floor and lift test. In the two subscales of FABQ, 47 percent had more fear in physical activity component and 27 percent had more fear in work component. The scores of BPS and FABQ were correlated using Pearson's correlation test showed strong positive correlation (r = 0.685, P value < 0.01). Higher scores on FABQ are indicative of greater fear and avoidance beliefs. Higher scores on the FABQ 47% in physical activity and 27% in work component are indicative of greater fear and avoidance beliefs. A strong relationship exists between elevated fear avoidance beliefs (FABQ) and activity limitation (BPS) in patients with chronic low back pain.


p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both.
Mitochondria sustain damage with aging, and the resulting mitochondrial dysfunction has been implicated in a number of diseases including Parkinson disease. We recently demonstrated that the E3 ubiquitin ligase Parkin, which is linked to recessive forms of parkinsonism, causes a dramatic increase in mitophagy and a change in mitochondrial distribution, following its translocation from the cytosol to mitochondria. Investigating how Parkin induces these changes may offer insight into the mechanisms that lead to the sequestration and elimination of damaged mitochondria. We report that following Parkin's translocation from the cytosol to mitochondria, Parkin (but not a pathogenic mutant) promotes the K63-linked polyubiquitination of mitochondrial substrate(s) and recruits the ubiquitin- and LC3-binding protein, p62/SQSTM1, to mitochondria. After its recruitment, p62/SQSTM1 mediates the aggregation of dysfunctional mitochondria through polymerization via its PB1 domain, in a manner analogous to its aggregation of polyubiquitinated proteins. Surprisingly and in contrast to what has been recently reported for ubiquitin-induced pexophagy and xenophagy, p62 appears to be dispensable for mitophagy. Similarly, mitochondrial-anchored ubiquitin is sufficient to recruit p62 and promote mitochondrial clustering, but does not promote mitophagy. Although VDAC1 (but not VDAC2) is ubiquitinated following mitochondrial depolarization, we find VDAC1 cannot fully account for the mitochondrial K63-linked ubiquitin immunoreactivity observed following depolarization, as it is also observed in VDAC1/3-/- mouse embryonic fibroblasts. Additionally, we find VDAC1 and VDAC3 are dispensable for the recruitment of p62, mitochondrial clustering and mitophagy. These results demonstrate that mitochondria are aggregated by p62, following its recruitment by Parkin in a VDAC1-independent manner. They also suggest that proteins other than p62 are likely required for mitophagy downstream of Parkin substrates other than VDAC1.


Does Changing the Age of a Child to be Considered in 3-Level Version of EQ-5D-Y Discrete Choice Experiment-Based Valuation Studies Affect Health Preferences?
There has been some debate about the choice of perspective and the age of the child considered when completing preference elicitation tasks in the 3-level version of EQ-5D-Y (EQ-5D-Y-3L) valuation protocol. This study aimed to clarify the impact on latent scale EQ-5D-Y-3L values of varying the age of the child experiencing the health state considered by respondents completing the discrete choice experiment (DCE) tasks of the protocol. We conducted an online DCE with a representative sample of 1000 adults in the United Kingdom and 1000 adults in the United States. Respondents selected the health state they prefer from a series of DCE paired EQ-5D-Y-3L health state comparisons using their own perspective and that of a hypothetical child from the following age groups: "5-7 years old," "8-10 years old," "11-13 years old," and "14-15 years old." Data analysis was conducted using separate multinomial logit models for each perspective and country. We also estimated combined models including data from each possible pair of perspectives and used interactions between EQ-5D-Y-3L levels and perspective to determine whether any differences were statistically significant. No statistically significant differences in coefficients between perspectives were found in the United States. In the United Kingdom, there were differences between the own perspective and the 5 to 7 years old perspective (looking after myself level 3) and between the 5 to 7 years old perspective and the 8 to 10 years old perspective (usual activities level 3). Our results suggest that there is minimal impact on latent scale values when using different ages of the hypothetical child in the current EQ-5D-Y-3L valuation protocol.


Turning the tide: national policy approaches to increasing physical activity in seven European countries.
Physical inactivity is one of the four leading behavioural risk factors for non-communicable disease (NCD). Like tobacco control, increasing levels of health-enhancing physical activity (HEPA) will require a national policy framework providing direction and a clear set of actions. Despite frequent calls, there has been insufficient progress on policy development in the majority of countries around the world. This study sought and summarised national HEPA policy in seven European countries (Finland, Italy, the Netherlands, Norway, Portugal, Slovenia and Switzerland). Data collection used a policy audit tool (PAT), a 27-item instrument structured into four sections. All countries reported some legislation or policy across the sectors of education, sport and health. Only some countries reported supportive policy in the transport and environment sectors. Five countries reported a stand-alone HEPA policy and six countries reported national recommendations. HEPA prevalence targets varied in magnitude and specificity and the presence of other relevant goals from different sectors highlighted the opportunity for joint action. Evaluation and the use of scientific evidence were endorsed but described as weak in practice. Only two countries reported a national multisector coordinating committee and most countries reported challenges with partnerships on different levels of policy implementation. Bringing together the key components for success within a national HEPA policy framework is not simple. This in-depth policy audit and country comparison highlighted similarities and differences and revealed new opportunities for consideration by other countries. These examples can inform countries within and beyond Europe and guide the development of national HEPA policy within the NCD prevention agenda.


Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis.
Cilia and extracellular vesicles (EVs) are signaling organelles [1]. Cilia act as cellular sensory antennae, with defects resulting in human ciliopathies. Cilia both release and bind to EVs [1]. EVs are sub-micron-sized particles released by cells and function in both short- and long-range intercellular communication. In C. elegans and mammals, the autosomal dominant polycystic kidney disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation [2]. A fundamental understanding of EV biology and the relationship between the polycystins, cilia, and EVs is lacking. To define properties of a ciliated EV-releasing cell, we performed RNA-seq on 27 GFP-labeled EV-releasing neurons (EVNs) isolated from adult C. elegans. We identified 335 significantly overrepresented genes, of which 61 were validated by GFP reporters. The EVN transcriptional profile uncovered new pathways controlling EV biogenesis and polycystin signaling and also identified EV cargo, which included an antimicrobial peptide and ASIC channel. Tumor-necrosis-associated factor (TRAF) homologs trf-1 and trf-2 and the p38 mitogen-activated protein kinase (MAPK) pmk-1 acted in polycystin-signaling pathways controlling male mating behaviors. pmk-1 was also required for EV biogenesis, independent of the innate immunity MAPK signaling cascade. This first high-resolution transcriptome profile of a subtype of ciliated sensory neurons isolated from adult animals reveals the functional components of an EVN.


Use of quality measures for Medicaid behavioral health services by state agencies: implications for health care reform.
The structure-process-outcome quality framework espoused by Donabedian provides a conceptual way to examine and prioritize behavioral health quality measures used by states. This report presents an environmental scan of the quality measures and satisfaction surveys that state Medicaid managed care and behavioral health agencies used prior to Medicaid expansion in 2014. Data were collected by reviewing online documents related to Medicaid managed care contracts for behavioral health, quality strategies, quality improvement plans, quality and performance indicators data, annual outcomes reports, performance measure specification manuals, legislative reports, and Medicaid waiver requests for proposals. Information was publicly available for 29 states. Most states relied on process measures, along with some structure and outcome measures. Although all states reported on at least one process measure of behavioral health quality, 52% of states did not use any outcomes measures and 48% of states had no structure measures. A majority of the states (69%) used behavioral health measures from the National Committee for Quality Assurance's Healthcare Effectiveness Data and Information Set, and all but one state in the sample (97%) used consumer experience-of-care surveys. Many states supplemented these data with locally developed behavioral health indicators that rely on administrative and nonadministrative data. State Medicaid agencies are using nationally recognized as well as local measures to assess quality of behavioral health care. Findings indicate a need for additional nationally endorsed measures in the area of substance use disorders and treatment outcomes.


Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.
Diabetes and atherosclerosis have been proposed to be influenced by immune and autoimmune mechanisms. A common incriminated antigen in both disorders is the heat shock protein (HSP)-60/65. In the current study, we established a model combining hyperglycemia with hyperlipidemia in LDL receptor-deficient (LDL-RD) mice and assessed its possible influences on lipid profile, HSP60/65, and atherogenesis. LDL-RD mice were injected either with streptozotocin to induce hyperglycemia or with citrate buffer (control). When hyperglycemia was induced, both study groups were challenged with a high-fat (Western) diet for 6 weeks. Plasma fasting glucose, lipid profile, and antibody levels to HSP65 and oxidized LDL were assessed. At death, the spleens from both groups were evaluated for their proliferative response to HSP65 and the consequent cytokine production. The extent of atherosclerosis was assessed at the aortic sinus. Plasma glucose, cholesterol, and triglyceride levels were elevated in mice injected with streptozotocin compared with control mice. Atherosclerotic lesions were significantly larger in the streptozotocin-injected hyperglycemic LDL-RD mice (132 +/- 23 x 10(5) microm2) in comparison to their normoglycemic litter-mates (20 +/- 6.6 x 10(5) microm2; P < 0.0001). Both humoral and cellular immune response to HSP65 was more pronounced in streptozotocin-injected mice. When challenged with HSP65 in vitro, splenocytes from streptozotocin-injected mice favored the production of the T-helper (TH)-1 cytokine gamma-interferon. In conclusion, we have established a mouse model that combines hyperglycemia with diet-induced hyperlipidemia in LDL-RD mice and studied its effect on atherosclerosis progression. The accelerated atherosclerotic process is associated with heightened immune response to HSP65 and a shift to a TH1 cytokine profile.


Spiritual well-being and hope in the preoperative period of cardiac surgery.
To characterize relations between spiritual well-being and hope of patients in the preoperative period of cardiac surgery. Exploratory cross-sectional study with quantitative approach, performed in the infirmaries of a reference hospital in cardiology. We evaluated 69 patients hospitalized in preoperative period of myocardial revascularization, valve repair or replacement. We verified that patients hold relevant scores of hope and welfare in all areas, being the existential well-being significantly lower than the religious one. The average of the spiritual well-being score was below the required to be considered high. There was no significant correlation between welfare and hope. Nurses should develop a watchful eye to these issues, be trained in specific protocols of spiritual anamnese and use the real moments of care to strengthen the patients.


The beneficial attributes of visual art-making in cancer care: An integrative review.
We seek to understand what is known about the use of visual art-making for people who have a cancer diagnosis, and to explore how art-making may help address fatigue in the cancer care context. Art-making involves creating art or craft alone or in a group and does not require an art-therapist as the emphasis is on creativity rather than an overt therapeutic intention. An integrative review was undertaken of qualitative, quantitative and mixed-method studies on art-making for people who have cancer, at any stage of treatment or recovery. An adapted version of Kaplan's Attention Restoration Theory (ART) was used to interpret the themes found in the literature. Fifteen studies were reviewed. Nine concerned art-making programmes and six were focused on individual, non-facilitated art-making. Review results suggested that programme-based art-making may provide participants with opportunities for learning about self, support, enjoyment and distraction. Individual art-making can provides learning about self, diversion and pleasure, self-management of pain, a sense of control, and enhanced social relationships. When viewed through the lens of ART, art-making can be understood as an energy-restoring activity that has the potential to enhance the lives of people with a diagnosis of cancer.


Objective and subjective visual quality after implantation of all optic zone diffractive multifocal intraocular lenses: a prospective, case-control observational study.
To evaluate the objective and subjective optical quality of all optic zone diffractive multifocal intraocular lens (IOL). Fifty patients (50 eyes) having phacoemulsification and IOL implantation surgery were enrolled. 25 patients were implanted with all optic zone diffractive multifocal IOL and 25 patients with monofocal IOL. Objective optical quality parameters under 4 mm pupil using Optical Quality Analysis System (OQAS), subjective visual acuity (VA) at 85 cd/m2 luminance and questionnaire concerning halo and visual function were assessed. The multifocal group gained similar objective optical outcomes, such as OQAS values at contrast 100%, 20%, 9%, modulation transfer function cut-off and Strehl ratio, as the monofocal group. Objective scatter index (OSI) was significantly better in the monofocal group. Distance corrected near VA, uncorrected near VA, distance corrected intermediate VA and uncorrected intermediate VA were significantly better in the multifocal group. The difference in uncorrected distance VA and best corrected distance VA between the monofocal and multifocal groups was not significant. Mild halos and glare were reported in both groups and a significant difference between the two groups was not observed; however, moderate glare and halos were reported only in the multifocal group (2/25). There was no significant difference between the two groups when visual function was compared. All optic zone diffractive multifocal IOLs provided almost the same objective optical quality as monofocal IOLs did under 4 mm pupil besides good all distance visual performance, but with greater OSI, indicating that implantation provides good optical quality in daytime but with more intraocular scatter light. NCT02234635, post-results.


Atomistic QM/MM simulations of the strength of covalent interfaces in carbon nanotube-polymer composites.
We investigate the failure of carbon-nanotube/polymer composites by using a recently-developed hybrid quantum-mechanical/molecular-mechanical (QM/MM) approach to simulate nanotube pull-out from a cross-linked polyethene matrix. Our study focuses on the strength and failure modes of covalently-bonded nanotube-polymer interfaces based on amine, carbene and carboxyl functional groups and a [2+1] cycloaddition. We find that the choice of the functional group linking the polymer matrix to the nanotube determines the effective strength of the interface, which can be increased by up to 50% (up to the limit dictated by the strength of the polymer backbone itself) by choosing groups with higher interfacial binding energy. We rank the functional groups presented in this work based on the strength of the resulting interface and suggest broad guidelines for the rational design of nanotube functionalisation for nanotube-polymer composites.


Dissection of agonistic and blocking effects of CD200 receptor antibodies.
The CD200 receptor (CD200R) is present mainly on myeloid cells and gives inhibitory signals when engaged by its ligand CD200. The interaction is currently of therapeutic interest in cancer and inflammation. However functional effects are complicated by the fact that CD200R is itself polymorphic and also a member of a paired receptor family with four closely related gene products in mice called CD200RLa etc. We show that a second allele of CD200R (termed CD200R(2)) that differs in 7 amino acids also binds CD200 but did not react with the widely used CD200R antibody OX110. Biochemical and functional analysis showed that the CD200/CD200R interaction was blocked by the OX131, mAb that recognises both CD200R(1) and CD200R(2), but not by OX110 mAb. Both mAb can give agonistic inhibitory signals but functional analysis shows OX131 mAb also has the potential to block inhibition by preventing the ligand-receptor interaction and hence gives opposing effects. Although OX131 mAb cross-reacts with the activating receptor CD200RLe, it is specific for CD200R in C57BL/6 whilst OX110 mAb cross-reacts on CD200RLc. The results show the importance of the repertoire of paired receptors in strains or individuals and mAb used with implications for paired receptor analysis and therapeutics.


Proteinuria during dengue fever in children.
This study aimed to investigate proteinuria occurring during dengue disease in children and assess if measurement of this parameter can help physicians in the clinical management of patients. Proteinuria was assessed by dipstick and quantified by urine protein:creatinine ratio (UPCR) in samples from patients hospitalized with a confirmed dengue infection and in healthy controls. The dipstick tested positive in 42.9% of the patients presenting at hospital with dengue versus 20.0% in healthy controls. UPCR increased during the critical phase of the disease; peaking one week after fever onset then decreasing as the patients recovered. Patients with warnings signs or severe dengue were more likely to present with proteinuria detected by UPCR at the time of hospital admission compared to patients without warning signs. The sensitivity of this marker, however, was limited as only 16.1% of the patients with warning signs had proteinuria. Urine dipstick and UPCR do not seem to be very valuable for the triage of the patients at the time of the initial consultation but the observation of a decrease of the UPCR during the course of the illness appears to indicate an evolution towards recovery.


Leptospira interrogans serovar copenhageni harbors two lexA genes involved in SOS response.
Bacteria activate a regulatory network in response to the challenges imposed by DNA damage to genetic material, known as the SOS response. This system is regulated by the RecA recombinase and by the transcriptional repressor lexA. Leptospira interrogans is a pathogen capable of surviving in the environment for weeks, being exposed to a great variety of stress agents and yet retaining its ability to infect the host. This study aims to investigate the behavior of L. interrogans serovar Copenhageni after the stress induced by DNA damage. We show that L. interrogans serovar Copenhageni genome contains two genes encoding putative LexA proteins (lexA1 and lexA2) one of them being potentially acquired by lateral gene transfer. Both genes are induced after DNA damage, but the steady state levels of both LexA proteins drop, probably due to auto-proteolytic activity triggered in this condition. In addition, seven other genes were up-regulated following UV-C irradiation, recA, recN, dinP, and four genes encoding hypothetical proteins. This set of genes is potentially regulated by LexA1, as it showed binding to their promoter regions. All these regions contain degenerated sequences in relation to the previously described SOS box, TTTGN 5CAAA. On the other hand, LexA2 was able to bind to the palindrome TTGTAN10TACAA, found in its own promoter region, but not in the others. Therefore, the L. interrogans serovar Copenhageni SOS regulon may be even more complex, as a result of LexA1 and LexA2 binding to divergent motifs. New possibilities for DNA damage response in Leptospira are expected, with potential influence in other biological responses such as virulence.


Headaches and the N95 face-mask amongst healthcare providers.
During the 2003 severe acute respiratory distress syndrome epidemic, healthcare workers mandatorily wore the protective N95 face-mask. We administered a survey to healthcare workers to determine risk factors associated with development of headaches (frequency, headache subtypes and duration of face-mask wear) and the impact of headaches (sick days, headache frequency and use of abortive/preventive headache medications). In the survey, 212 (47 male, 165 female) healthcare workers of mean age 31 years (range, 21-58) participated. Of the 79 (37.3%) respondents who reported face-mask-associated headaches, 26 (32.9%) reported headache frequency exceeding six times per month. Six (7.6%) had taken sick leave from March 2003 to June 2004 (mean 2 days; range 1-4 days) and 47 (59.5%) required use of abortive analgesics because of headache. Four (2.1%) took preventive medications for headaches during this period. Multivariate logistic regression showed that pre-existing headaches [P = 0.041, OR = 1.97 (95% CI 1.03-3.77)] and continuous use of the N95 face-mask exceeding 4 h [P = 0.053, OR = 1.85 (95% CI 0.99-3.43)] were associated with development of headaches. Healthcare providers may develop headaches following the use of the N95 face-mask. Shorter duration of face-mask wear may reduce the frequency and severity of these headaches.


Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages.
To survive and replicate in macrophages Mycobacterium tuberculosis (Mtb) has developed strategies to subvert host defence mechanisms, including autophagy. Autophagy induction has the potential to clear Mtb, but little is known about its effect during controlled tuberculosis and HIV co-infection. Mammalian target of rapamycin complex1 (mTORC1) inhibitors were used to induce autophagy in human macrophages pre-infected with HIV-1BaL and infected with a low dose of Mtb (co-infected), or single Mtb infected (single infected). The controlled Mtb infection was disrupted upon mTOR inhibition resulting in increased Mtb replication in a dose-dependent manner which was more pronounced during co-infection. The increased Mtb replication could be explained by the marked reduction in phagosome acidification upon mTOR inhibition. Autophagy stimulation targeting mTORC1 clearly induced a basal autophagy with flux that was unlinked to the subcellular environment of the Mtb vacuoles, which showed a concurrent suppression in acidification and maturation/flux. Overall our findings indicate that mTOR inhibition during Mtb or HIV/Mtb co-infection interferes with phagosomal maturation, thereby supporting mycobacterial growth during low-dose and controlled infection. Therefore pharmacological induction of autophagy through targeting of the canonical mTORC1-pathway should be handled with caution during controlled tuberculosis, since this could have serious consequences for patients with HIV/Mtb co-infection.


How do you modernize a health service? A realist evaluation of whole-scale transformation in london.
Large-scale, whole-systems interventions in health care require imaginative approaches to evaluation that go beyond assessing progress against predefined goals and milestones. This project evaluated a major change effort in inner London, funded by a charitable donation of approximately $21 million, which spanned four large health care organizations, covered three services (stroke, kidney, and sexual health), and sought to "modernize" these services with a view to making health care more efficient, effective, and patient centered. This organizational case study draws on the principles of realist evaluation, a largely qualitative approach that is centrally concerned with testing and refining program theories by exploring the complex and dynamic interaction among context, mechanism, and outcome. This approach used multiple data sources and methods in a pragmatic and reflexive manner to build a picture of the case and follow its fortunes over the three-year study period. The methods included ethnographic observation, semistructured interviews, and scrutiny of documents and other contemporaneous materials. As well as providing ongoing formative feedback to the change teams in specific areas of activity, we undertook a more abstract, interpretive analysis, which explored the context-mechanism-outcome relationship using the guiding question "what works, for whom, under what circumstances?" In this example of large-scale service transformation, numerous projects and subprojects emerged, fed into one another, and evolved over time. Six broad mechanisms appeared to be driving the efforts of change agents: integrating services across providers, finding and using evidence, involving service users in the modernization effort, supporting self-care, developing the workforce, and extending the range of services. Within each of these mechanisms, different teams chose widely differing approaches and met with differing success. The realist analysis of the fortunes of different subprojects identified aspects of context and mechanism that accounted for observed outcomes (both intended and unintended). This study was one of the first applications of realist evaluation to a large-scale change effort in health care. Even when an ambitious change program shifts from its original goals and meets unforeseen challenges (indeed, precisely because the program morphs and adapts over time), realist evaluation can draw useful lessons about how particular preconditions make particular outcomes more likely, even though it cannot produce predictive guidance or a simple recipe for success. Noting recent calls by others for the greater use of realist evaluation in health care, this article considers some of the challenges and limitations of this method in the light of this experience and suggests that its use will require some fundamental changes in the worldview of some health services researchers.


Implications of the angiographic string sign in carotid atherosclerosis.
We identified 60 patients (42 men and 18 women with an average age of 62.6 years) with angiographically documented carotid stenoses of greater than or equal to 95%; a string sign was demonstrated in 28. Twenty of the 60 patients (33%) were asymptomatic on presentation, 26 (43%) had hemispheric transient ischemic attacks, 21 (35%) had amaurosis fugax, and nine (15%) had previous ipsilateral infarctions. Demographics, mode of presentation, and prevalence of atherosclerotic risk factors were not significantly different between patients with and without a string sign. Doppler frequencies recorded in patients with a string sign were less than 6 or greater than 16 KHz. Real-time ultrasonography imaged a patent lumen in all but three cases with a string sign. Surgery was performed in 26 patients with a string sign and in 21 patients without a string sign. The rate of major perioperative complications was not influenced by the presence of a string sign, contralateral extracranial stenosis, or ipsilateral siphon stenosis. Average lumen size of the endarterectomy specimens was 0.94 mm in those with and 1.7 mm in those without a string sign. We conclude that combined noninvasive testing has a sensitivity of 83% for demonstrating a residual lumen in patients with greater than or equal to 95% carotid stenosis and that the angiographic string sign does not affect the mode of presentation or surgical outcome of these patients.