Enthesitis: Much More Than Focal Insertion Point Inflammation.
Recognition of the importance of enthesitis as the pivotal pathological process underpinning spondyloarthropathies (SpA) has increased in recent years. Thus, we summarized the current knowledge on the pathogenic role of enthesitis on SpA shown by both animal models and human studies in vivo. Experimental models have shown several SpA-like diseases that commence at entheses and are linked to nail disease as well as dactylitis, two important entheseal-associated conditions in humans. Frequently, enthesitis is not the primary outcome measure in studies of peripheral PsA and SpA although arguably it is the key parameter being indirectly assessed in spinal disease in ankylosing spondylitis. The use of different agents including JAK, IL-17, and IL-23 inhibitors contributes significantly to our understanding of enthesitis in terms of involved immune pathways. Enthesitis and enthesis organ inflammation may be the primary pathological process underlying SpA associated skeletal inflammation. Emergent studies are beginning to elucidate the molecular basis for this type of joint inflammatory response.


[Association between varioliform gastritis and cirrhosis].
Varioliform gastritis (VG) is found in approximately 0.3 to 2.8% of upper gastrointestinal endoscopies. Its etiology is not known. We have observed a higher frequency of VG in patients with liver cirrhosis. To confirm if there is an association between VG and liver cirrhosis. Two case-control studies were done. A retrospective study, reviewing the endoscopy database of a gastroenterological unit. A prospective study, identifying cases with the endoscopic diagnosis of VG among all patients referred for upper gastrointestinal endoscopies. The presence of liver cirrhosis, based on clinical, laboratory, ultrasonographic and endoscopic features was registered among patients with VG. VG was found in 549 of 11.659 upper gastrointestinal endoscopies. Fourteen percent of patients with VG had cirrhosis compared to 5.6% in control patients (c² 29,8; p < 0.01). The odds ratio (OR) for having cirrhosis of patients with VG was 9.3 (95% confidence intervals 3.4-25.5, p < 0,01), according to a logistic regression analysis. In the prospective study, that included 1.498 upper gastrointestinal endoscopies, VG was also significantly more common among patients with liver cirrhosis. A higher frequency of VG was found among patients with liver cirrhosis. Therefore, the endoscopic finding of VG should alert physicians to look for the presence of a coexistent liver cirrhosis.


Aetiology of congenital and paediatric cataract in an Australian population.
Paediatric cataract is a major cause of childhood blindness. Several genes associated with congenital and paediatric cataracts have been identified. The aim was to determine the incidence of cataract in a population, the proportion of hereditary cataracts, the mode of inheritance, and the clinical presentation. The Royal Children's Hospital and the Royal Victorian Eye and Ear Hospital have a referral base for almost all paediatric patients with cataracts in south eastern Australia. The database contains cases seen over the past 25 years. The medical histories of these patients were reviewed. 421 patients with paediatric cataract were identified, which gives an estimated incidence of 2.2 per 10,000 births. Of the 342 affected individuals with a negative family history, 50% were diagnosed during the first year of life, and 56/342 (16%) were associated with a recognised systemic disease or syndrome. Unilateral cataract was identified in 178/342 (52%) of sporadic cases. 79 children (from 54 nuclear families) had a positive family history. Of these 54 families, 45 were recruited for clinical examination and DNA collection. Ten nuclear families were subsequently found to be related, resulting in four larger pedigrees. Thus, 39 families have been studied. The mode of inheritance was autosomal dominant in 30 families, X linked in four, autosomal recessive in two, and uncertain in three. In total, 178 affected family members were examined; of these 8% presented with unilateral cataracts and 43% were diagnosed within the first year of life. In the paediatric cataract population examined, approximately half of the patients were diagnosed in the first year of life. More than 18% had a positive family history of cataracts. Of patients with hereditary cataracts 8% presented with unilateral involvement. Identification of the genes that cause paediatric and congenital cataract should help clarify the aetiology of some sporadic and unilateral cataracts.


Sexual disorders in women with MS: assessment and management.
Summarize the data on sexual disorders in women with multiple sclerosis (MS). Review of 99 Pubmed articles covering sexual dysfunction in women with MS. Prevalence of dysfunction in women with MS varies from 34% to 85%. They include poor vaginal lubrication, poor clitoral erection, and anorgasmia, which correlate with level of disability. Specific brain stem and pyramidal lesions appear to correlate with anorgasmia. Age and duration of the disease correlate with sexual disorders, but not age at onset. Secondary consequences of MS, including bladder and bowel dysfunction, spasticity, pain, fatigue, depression, anxiety, and side effects of medication contribute to sexual dysfunction. Treatments can involve alpha-blockers or phosphodiesterase-5 inhibitors to increase smooth muscle relaxation, while lubricants and oestrogen therapy can help vaginal dryness, burning and dyspareunia. Antidepressants can delay (or abolish) orgasm, suggesting reducing dosage or combining them with PDE5 inhibitors. Counselling should emphasize planning sexual activities, reducing fatigue, managing positions, preventing incontinence, promoting sexual aids, extra-genital and other sexual options to achieve pleasurable and intimacy. Psychosocial interventions should include couples' relationship and communication skills to increase satisfaction. Sexual dysfunctions in women with MS are amenable to treatments covering primary, secondary and tertiary consequences of the disease.


Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with deficits in cognitive and motor functioning. While structural brain changes such as demyelination are an early hallmark of the disease, a characteristic profile of functional brain alterations in early MS is lacking. Functional neuroimaging studies at various disease stages have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in MS, with previous studies largely being limited to a static account of FC. Thus, it remains unclear how time-resolved FC relates to variance in clinical disability status in early MS. We here aimed to characterize brain network organization in early MS patients with time-resolved FC analysis and to explore the relationship between disability status, multi-domain clinical outcomes and altered network dynamics. Resting-state functional MRI (rs-fMRI) data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Based on the Expanded Disability Status Score (EDSS), patients were split into two sub-groups: patients without clinical disability (EDSS ≤ 1, n = 36) and patients with mild to moderate levels of disability (EDSS ≥ 2, n = 39). Five dynamic FC states were extracted from whole-brain rs-fMRI data. Group differences in static and dynamic FC strength, across-state overall connectivity, dwell time, transition frequency, modularity, and global connectivity were assessed. Patients' impairment was quantified as custom clinical outcome z-scores (higher: worse) for the domains depressive symptoms, fatigue, motor, vision, cognition, total brain atrophy, and lesion load. Correlation analyses between functional measures and clinical outcomes were performed with Spearman partial correlation analyses controlling for age. Patients with mild to moderate levels of disability exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients without disability and HCs. Worse symptoms in all clinical outcome domains were positively associated with EDSS scores. Furthermore, depressive symptom severity was positively related to functional dynamics as measured by state-specific global connectivity and default mode network connectivity with attention networks, while fatigue and motor impairment were related to reduced frontoparietal network connectivity with the basal ganglia. Despite comparably low impairment levels in early MS, we identified distinct connectivity alterations between patients with mild to moderate disability and those without disability, and these changes were sensitive to clinical outcomes in multiple domains. Furthermore, time-resolved analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with conventional static analyses, showing that accounting for temporal dynamics helps disentangle the relationship between functional alterations, disability status, and symptoms in early MS.


Modeling the Impact of White-Plague Coral Disease in Climate Change Scenarios.
Coral reefs are in global decline, with coral diseases increasing both in prevalence and in space, a situation that is expected only to worsen as future thermal stressors increase. Through intense surveillance, we have collected a unique and highly resolved dataset from the coral reef of Eilat (Israel, Red Sea), that documents the spatiotemporal dynamics of a White Plague Disease (WPD) outbreak over the course of a full season. Based on modern statistical methodologies, we develop a novel spatial epidemiological model that uses a maximum-likelihood procedure to fit the data and assess the transmission pattern of WPD. We link the model to sea surface temperature (SST) and test the possible effect of increasing temperatures on disease dynamics. Our results reveal that the likelihood of a susceptible coral to become infected is governed both by SST and by its spatial location relative to nearby infected corals. The model shows that the magnitude of WPD epidemics strongly depends on demographic circumstances; under one extreme, when recruitment is free-space regulated and coral density remains relatively constant, even an increase of only 0.5°C in SST can cause epidemics to double in magnitude. In reality, however, the spatial nature of transmission can effectively protect the community, restricting the magnitude of annual epidemics. This is because the probability of susceptible corals to become infected is negatively associated with coral density. Based on our findings, we expect that infectious diseases having a significant spatial component, such as Red-Sea WPD, will never lead to a complete destruction of the coral community under increased thermal stress. However, this also implies that signs of recovery of local coral communities may be misleading; indicative more of spatial dynamics than true rehabilitation of these communities. In contrast to earlier generic models, our approach captures dynamics of WPD both in space and time, accounting for the highly seasonal nature of annual WPD outbreaks.


Exploring the Factors Influencing Consumers to Voluntarily Reward Free Health Service Contributors in Online Health Communities: Empirical Study.
Rewarding health knowledge and health service contributors with money is one possible approach for the sustainable provision of health knowledge and health services in online health communities (OHCs); however, the reasons why consumers voluntarily reward free health knowledge and health service contributors are still underinvestigated. This study aimed to address the abovementioned gap by exploring the factors influencing consumers' voluntary rewarding behaviors (VRBs) toward contributors of free health services in OHCs. On the basis of prior studies and the cognitive-experiential self-theory (CEST), we incorporated two health service content-related variables (ie, informational support and emotional support) and two interpersonal factors (ie, social norm compliance and social interaction) and built a proposed model. We crawled a dataset from a Chinese OHC for mental health, coded it, extracted nine variables, and tested the model with a negative binomial model. The data sample included 2148 health-related questions and 12,133 answers. The empirical results indicated that the effects of informational support (β=.168; P<.001), emotional support (β=.463; P<.001), social norm compliance (β=.510; P<.001), and social interaction (β=.281; P<.001) were significant. The moderating effects of social interaction on informational support (β=.032; P=.02) and emotional support (β=-.086; P<.001) were significant. The moderating effect of social interaction on social norm compliance (β=.014; P=.38) was insignificant. Informational support, emotional support, social norm compliance, and social interaction positively influence consumers to voluntarily reward free online health service contributors. Social interaction enhances the effect of informational support but weakens the effect of emotional support. This study contributes to the literature on knowledge sharing in OHCs by exploring the factors influencing consumers' VRBs toward free online health service contributors and contributes to the CEST literature by verifying that the effects of experiential and rational systems on individual behaviors can vary while external factors change.


The G-protein βγ subunits regulate platelet function.
G-protein coupled receptors (GPCRs) tightly regulate platelet function by interacting with various physiological agonists. An essential mediator of GPCR signaling is the G protein αβγ heterotrimers, in which the βγ subunits are central players in downstream signaling. Herein, we investigated the role of Gβγ subunits in platelet function, hemostasis and thrombogenesis. To achieve this goal, platelets from both mice and humans were employed in the context of a small molecule inhibitor of Gβγ, namely gallein. We used an aggregometer to examine aggregation and dense granules secretion. We also used flow cytometry for P-selectin and PAC1 to determine the impact of inhibiting Gβγ on α -granule secretion and αIIbβ3 activation. Clot retraction and the platelet spreading assay were used to examine Gβγ role in outside-in platelet signaling, whereas Western blot was employed to examine its role in Akt activation. Finally, we used the bleeding time assay and the FeCl3-induced carotid-artery injury thrombosis model to determine Gβγ contribution to in vivo platelet function. We observed that gallein inhibits platelet aggregation and secretion in response to agonist stimulation, in both mouse and human platelets. Furthermore, gallein also exerted inhibitory effects on integrin αIIbβ3 activation, clot retraction, platelet spreading and Akt activation/phosphorylation. Finally, gallein's inhibitory effects manifested in vivo, as documented by its ability to modulate physiological hemostasis and delay thrombus formation. Our findings demonstrate, for the first time, that Gβγ subunits directly regulate GPCR-dependent platelet function, in vitro and in vivo. Moreover, these data highlight Gβγ as a novel therapeutic target for managing thrombotic disorders.


Reproductive success is driven by local site fidelity despite stronger specialisation by individuals for large-scale habitat preference.
There is widespread evidence that within populations, specialists and generalists can coexist and this is particularly prevalent in marine ecosystems, where foraging specialisations are evident. While individuals may limit niche overlap by consistently foraging in specific areas, site fidelity may also emerge as an artefact of habitat choice, but both drivers and fitness consequences of site fidelity are poorly understood. Here, we examine an individual metric of site and habitat fidelity, using tracking data collected over 11 years for black-browed albatrosses (Thalassarche melanophris). Fidelity was calculated as the similarity between pairs of foraging zones, quantifying measures for within and between years. Foraging areas were identified using area-restricted search, defined as periods during which birds decrease speed and increase turning. Our results demonstrate that birds were considerably more specialised in the habitat in which they forage than the exact location they use within years, and there was a similar pattern between years. However, despite this, it was site fidelity that explained reproductive success. Within a single year, females which were more faithful to a specific location had higher reproductive success than non-specialists, and between years there was a tendency for both sexes. Our results suggest that black-browed albatrosses are highly faithful in their foraging habitat but it is rather site fidelity that is more clearly associated with reproductive success.


Consistency, precision, and accuracy of optical and electromagnetic shape-capturing systems for digital measurement of residual-limb anthropometrics of persons with transtibial amputation.
Computer-aided design (CAD) and computer-aided manufacturing systems have been adapted for specific use in prosthetics, providing practitioners with a means to digitally capture the shape of a patient's limb, modify the socket model using software, and automatically manufacture either a positive model to be used in the fabrication of a socket or the socket itself. The digital shape captured is a three-dimensional (3-D) model from which standard anthropometric measures can be easily obtained. This study recorded six common anthropometric dimensions from CAD shape files of three foam positive models of the residual limbs of persons with transtibial amputations. Two systems were used to obtain 3-D models of the residual limb, a noncontact optical system and a contact-based electromagnetic field system, and both experienced practitioners and prosthetics students conducted measurements. Measurements were consistent; the mean range (difference of maximum and minimum) across all measurements was 0.96 cm. Both systems provided similar results, and both groups used the systems consistently. Students were slightly more consistent than practitioners but not to a clinically significant degree. Results also compared favorably with traditional measurement, with differences versus hand measurements about 5 mm. These results suggest the routine use of digital shape capture for collection of patient volume information.


Highly reflective nanofiber films based on electrospinning and their application on color uniformity and luminous efficacy improvement of white light-emitting diodes.
Based on electrospinning technology, in this study, we fabricated poly(lactic-co-glycolic acid) (PLGA) nanofiber films with high reflectivity and scattering properties. Various films with different thicknesses and fiber diameters were fabricated by changing the electrospinning time and solution concentration, respectively. Detailed optical measurements demonstrate that the film reflectance and scattering ability increase with the thickness, whereas fiber diameter contributes little to both properties. With optimized film thickness and fiber diameter, nanofiber films feature whiteness with a reflectance of 98.8% compared to the BaSO4 white plate. Furthermore, when deposited on the reflector surface of a remote phosphor-converted light-emitting diode lamp, nanofiber films witness a correlated color temperature deviation decrease from 8880 K to 1407 K and a luminous efficiency improvement of 11.66% at 350 mA. Therefore, the nanofiber films can be applied in lighting systems as a highly reflective coating to improve their light efficacy and quality.


The response of a MOSFET, p-type semiconductor and LiF TLD to quasi-monoenergetic x-rays.
A metal oxide semiconductor field effect transistor (MOSFET), p-type semiconductor and a TLD can all be used for x-ray dosimetry, with each system having the common disadvantage of a response which is dependent upon the incident photon energy, particularly for energies < 1 MeV. A Pantak HF-320 quasi-monoenergetic x-ray unit was used to determine the response of two Thomson and Nielson TN-502RD MOSFETs, a Scanditronix EDP-10 semiconductor (build-up cap 10 mm: tissue equivalence), an EDD-5 semiconductor (build-up cap 4.5 mm: tissue equivalence) and an Lif:Mg:Ti TLD over the energy range 12-208 keV. The sensitivity of each detector was normalized to the value produced by exposure to 6 MV x-rays. The maximum relative sensitivities of the two MOSFET detectors were 4.19 +/- 0.25 and 4.44 +/- 0.26 respectively, occurring at an incident x-ray energy of 33 keV. The maximum relative sensitivity of the Scanditronix EDP-10 of 2.24 +/- 0.13 occurred at 65 keV, and for the EDD-5, it was 7.72 +/- 0.45 at 48 keV. The TLD produced a maximum relative sensitivity of 1.31 +/- 0.09 at 33 keV. Compared with available data based on heteroenergetic x-ray sources, these measurements have identified a more representative response for each detector to low-energy x-rays.


The Quantification of Representative Sequences pipeline for amplicon sequencing: case study on within-population ITS1 sequence variation in a microparasite infecting Daphnia.
Next generation sequencing (NGS) platforms are replacing traditional molecular biology protocols like cloning and Sanger sequencing. However, accuracy of NGS platforms has rarely been measured when quantifying relative frequencies of genotypes or taxa within populations. Here we developed a new bioinformatic pipeline (QRS) that pools similar sequence variants and estimates their frequencies in NGS data sets from populations or communities. We tested whether the estimated frequency of representative sequences, generated by 454 amplicon sequencing, differs significantly from that obtained by Sanger sequencing of cloned PCR products. This was performed by analysing sequence variation of the highly variable first internal transcribed spacer (ITS1) of the ichthyosporean Caullerya mesnili, a microparasite of cladocerans of the genus Daphnia. This analysis also serves as a case example of the usage of this pipeline to study within-population variation. Additionally, a public Illumina data set was used to validate the pipeline on community-level data. Overall, there was a good correspondence in absolute frequencies of C. mesnili ITS1 sequences obtained from Sanger and 454 platforms. Furthermore, analyses of molecular variance (amova) revealed that population structure of C. mesnili differs across lakes and years independently of the sequencing platform. Our results support not only the usefulness of amplicon sequencing data for studies of within-population structure but also the successful application of the QRS pipeline on Illumina-generated data. The QRS pipeline is freely available together with its documentation under GNU Public Licence version 3 at http://code.google.com/p/quantification-representative-sequences.


Ethnic identity: similarities and differences in white groups based on cultural practices.
The present study examined variability in ethnic identity among the ethnic groups that comprise the White racial category. Based on participants' ethnic self-labels, high school and college students (n = 495) were assigned to one of six groups: Armenian, Greek, Jewish, European, Mixed White ancestry ("Irish and Italian"), and Pan-ethnic ("White"). Individuals who identified with Specific White groups (Armenian, Greek, Jewish) had higher ethnic identity scores than individuals who identified with Nonspecific White groups (European, Mixed, Pan-ethnic). Specific White groups also had more heritage education, ethnic language competency, and religious participation than Nonspecific White groups. Regression analyses indicated that ethnic language competency and religious participation positively predicted ethnic identity for both Specific and Nonspecific White groups, controlling for age, sex, and generation. For the Specific White group, heritage education interacted with ethnic language to increase ethnic identity for students with low (but not medium or high) competency.


Plant biotechnology patents: applications in agriculture and medicine.
Recent advances in agricultural biotechnology have enabled the field of plant biology to move forward in great leaps and bounds. In particular, recent breakthroughs in molecular biology, plant genomics and crop science have brought about a paradigm shift of thought regarding the manner by which plants can be utilized both in agriculture and in medicine. Besides the more well known improvements in agronomic traits of crops such as disease resistance and drought tolerance, plants can now be associated with topics as diverse as biofuel production, phytoremediation, the improvement of nutritional qualities in edible plants, the identification of compounds for medicinal purposes in plants and the use of plants as therapeutic protein production platforms. This diversification of plant science has been accompanied by the great abundance of new patents issued in these fields and, as many of these inventions approach commercial realization, the subsequent increase in agriculturally-based industries. While this review chapter is written primarily for plant scientists who have great interest in the new directions being taken with respect to applications in agricultural biotechnology, those in other disciplines, such as medical researchers, environmental scientists and engineers, may find significant value in reading this article as well. The review attempts to provide an overview of the most recent patents issued for plant biotechnology with respect to both agriculture and medicine. The chapter concludes with the proposal that the combined driving forces of climate change, as well as the ever increasing needs for clean energy and food security will play a pivotal role in leading the direction for applied plant biotechnology research in the future.


The sequence of the bacteriophage P1 genome region serving as hot target for IS2 insertion.
A restriction fragment of the bacteriophage P1 genome known to serve as a hot target for IS2 insertion in its host, Escherichia coli K12, was entirely sequenced. It is 1756 bp long and it contains four long open reading frames, all in the same orientation. The two middle frames overlap partially. Eight of the nine studied IS2 insertions affecting phage reproduction map within three of these reading frames. No common feature was found between the nine target sites which have served for IS2 integration. However, there are two structural elements which might possibly contribute to rendering the studied DNA segment a hot region for IS2 insertion. The first is formed by two neighbouring, 30 and 40 bp regions of homology with an internal segment of IS2. The second is the pentanucleotide 5' GGTAT3', which is carried nine times in the sequenced fragment and which is found always in at least one copy within a variable distance of less than 100 bp of each inserted IS2 element.


Antiarrhythmics in Cardiac Arrest: A Systematic Review and Meta-Analysis.
It is widely accepted that antiarrhythmics play a role in cardiopulmonary resuscitation (CPR) universally, but the absolute benefit of antiarrhythmic use and the drug of choice in advanced life support remains controversial. To perform a thorough, in-depth review and analysis of current literature to assess the efficacy of antiarrhythmics in advanced life support. Two authors systematically searched through multiple bibliographic databases including CINAHL, SCOPUS, PubMed, Web of Science, Medline(Ovid) and the Cochrane Clinical Trials Registry. To be included studies had to compare an antiarrhythmic to either a control group, placebo or another antiarrhythmic in adult cardiac arrests. These studies were independently screened for outcomes in cardiac arrest assessing the effect of antiarrhythmics on return of spontaneous circulation (ROSC), survival and neurological outcomes. Data was extracted independently, compared for homogeneity and level of evidence was evaluated using the Cochrane Collaboration's tool for assessing the risk of bias. The Mantel-Haenszel (M-H) random effects model was used and heterogeneity was assessed using the I2 statistic. The search of the literature yielded 30 studies, including 39,914 patients. Eight antiarrhythmic agents were identified. Amiodarone and lidocaine, the two most commonly used agents, showed no significant effect on any outcome either against placebo or each other. Small low quality studies showed benefits in isolated outcomes with esmolol and bretylium against placebo. The only significant benefit of one antiarrhythmic over another was demonstrated with nifekalant over lidocaine for survival to admission (p=0.003). On sensitivity analysis of a small number of high quality level one RCTs, both amiodarone and lidocaine had a significant increase in survival to admission, with no effect on survival to discharge. This systematic review and meta-analysis suggests that, based on current literature and data, there has been no conclusive evidence that any antiarrhythmic agents improve rates of ROSC, survival to admission, survival to discharge or neurological outcomes. Given the side effects of some of these agents, we recommend further research into their utility in current cardiopulmonary resuscitation guidelines.


Surface-induced x-ray reflection visualization of membrane orientation and fusion into multibilayers.
The fusion of lipid membranes at the air-water interface has been detected with the use of x-ray reflection as a high-resolution, surface-sensitive technique. The rate of this fusion for dimyristoylphosphatidylcholine (DMPC) bilayers is the highest at 29 degrees C, which coincides with the chain-melting phase-transition temperature for the top membrane layers. After 6 hours of incubation a stack of at least ten surface-ordered membrane bilayers in equilibrium with the bulk vesicle suspension is formed. Such fusion is thus surface-catalyzed but not restricted to the first surface layer. The process involves partial membrane dehydration near the solution surface which decreases toward the bulk.


Heterogeneous Strain Distribution of Elastomer Substrates To Enhance the Sensitivity of Stretchable Strain Sensors.
Stretchable strain sensors, which convert mechanical stimuli into electrical signals, largely fuel the growth of wearable bioelectronics due to the ubiquitous, health-related strain in biological systems. In contrast to rigid conventional strain sensors, stretchable strain sensors present advantages of conformality and stretchability, solving the mechanical mismatch between electronics and the human body. However, the great challenge of stretchable strain sensors lies in achieving high sensitivity, which is required for both signal fidelity and cost considerations. Recent advances to solve this sensitivity challenge have focused on material optimization, in search of the optimum combination of conductive active materials and elastomer substrates among a myriad of artificial or natural materials. However, high sensitivity with a gauge factor larger than 50 remains a grand challenge, especially within large-strain regions. Here we present heterogeneous strain distribution of elastomer substrates as a powerful strategy to significantly enhance the sensitivity of stretchable strain sensors. The theoretical foundation of this strategy is mathematically proven on the basis of Ohm's law in electrics and mechanics of materials. First, the extent of the sensitivity enhancement is proved to be determined by the local strain in resistance-testing segments of heterogeneous strain sensors. Next, the local strain is proved to be quantitatively decided by material properties such as section area and Young's modulus. Thus, the necessary and sufficient condition to achieve high sensitivity in heterogeneous strain sensors is that the Young's modulus reciprocal or section area reciprocal in the resistance-testing segment is larger than the mean value. This provides a theoretical design guideline to achieve high sensitivity via heterogeneous strain distribution. On the basis of this guideline, we systematically summarize concrete instances of heterogeneity-induced sensitivity improvement in stretchable strain sensors, in sequence of increasing dimensionality. A typical example of a one-dimensional heterogeneous strain sensor is a structured fiber with microbeads, where the varied section area along the fiber axis results in heterogeneous strain and sensitivity improvement. Two-dimensional heterogeneous sensors in the form of thin films contain thickness gradient sensors and auxetic mechanical metamaterial sensors. The former exhibit heterogeneous section area via the self-pinning method, while the latter show heterogeneity in both the strain direction and amplitude, leading to a 24-fold improvement in sensitivity. Three-dimensional strain sensors include rationally structured sensors for out-of-plane force detection and asymmetric active materials in electronic whiskers. The resultant enhanced sensitivity in these heterogeneous strain sensors is beneficial for applications such as continuous health monitoring, biomedical diagnostics, and replacement prosthetics, taking advantage of augmented detection accuracy and declined device cost. Finally, we discuss possible future work in exploiting heterogeneous strain distributions, involving extended methodology to achieve heterogeneity, employing suppressed strain for stretchable electrodes, cyclic durability for long-term applications, and multifunctional system-level integration. We believe that this strategy of using heterogeneous strain distribution to enhance sensitivity can strongly promote the development of stretchable strain sensors for both practical and theoretical requirements.


Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy.
Cortical α-synuclein pathology plays a role in the development of cognitive dysfunction in both Parkinson's disease and dementia with Lewy bodies, although the causative cellular lesions have remained unclear. We aimed to address causal links between α-synuclein-driven pathology in the cerebral cortex and the development of cognitive impairments using new experimental models. Neuronal overexpression of human α-synuclein was induced in the rat medial prefrontal cortex using viral vectors. This was combined with inoculations of preformed fibrils of human α-synuclein in some animals. Rats were evaluated with tests probing prefrontal cognitive functions (delayed matching/nonmatching to position and 5-choice serial reaction time task). Patterns of neuropathology were characterized immunohistochemically. Neither α-synuclein overexpression nor the fibril seeds alone yielded any behavioral phenotype. In contrast, combining the 2 approaches produced significant impairments in working memory, attention, and inhibitory control. All animals injected with α-synuclein vectors exhibited high immunoreactivity for human α-synuclein in the medial prefrontal cortex and its primary projection targets. However, only when this overexpression was combined with fibril inoculations did animals exhibit large, proteinase K-resistant and Ser129 -phosphorylated α-synuclein intraneuronal inclusions in the medial prefrontal cortex and its closely interconnected brain regions. The inclusions were associated with distorted dendritic morphologies and partial neuronal loss in the targeted cortical areas. Cortical overexpression of human α-synuclein is not sufficient to produce cognitive dysfunction, whereas combining this overexpression with fibril seeds yields both cognitive and histopathological phenotypes that are relevant to human Lewy body disease. © 2019 International Parkinson and Movement Disorder Society.


Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are responsible for autosomal dominant and sporadic Parkinson disease (PD), possibly exerting their effects via a toxic gain of function. A common p.G2019S mutation (rs34637584:A>G) is responsible for up to 30-40% of PD cases in some ethnic populations. Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. LRRK2 mutants stimulated mitochondrial factors involved in apoptosis and induced production of reactive oxygen species (ROS) and oxidative modification of macromolecules. Furthermore, immunoblot and immunohistochemical analysis of postmortem human PD patients carrying the p.G2019S mutation showed a marked increase in phosphorylated PRDX3 (p-PRDX3) relative to normal brain. We showed that LRRK2 mutations increase the inhibition of an endogenous peroxidase by phosphorylation promoting dysregulation of mitochondrial function and oxidative damage. Our findings provide a mechanistic link between the enhanced kinase activity of PD-linked LRRK2 and neuronal cell death.


Alternative mapping of probes to genes for Affymetrix chips.
Short oligonucleotide arrays have several probes measuring the expression level of each target transcript. Therefore the selection of probes is a key component for the quality of measurements. However, once probes have been selected and synthesized on an array, it is still possible to re-evaluate the results using an updated mapping of probes to genes, taking into account the latest biological knowledge available. We investigated how probes found on recent commercial microarrays for human genes (Affymetrix HG-U133A) were matching a recent curated collection of human transcripts: the NCBI RefSeq database. We also built mappings and used them in place of the original probe to genes associations provided by the manufacturer of the arrays. In a large number of cases, 36%, the probes matching a reference sequence were consistent with the grouping of probes by the manufacturer of the chips. For the remaining cases there were discrepancies and we show how that can affect the analysis of data. While the probes on Affymetrix arrays remain the same for several years, the biological knowledge concerning the genomic sequences evolves rapidly. Using up-to-date knowledge can apparently change the outcome of an analysis.


[Neuromodulation in severe neuropathic pain].
Pain relief in patients with chronic neuropathic pain can be difficult to accomplish. If pharmacological treatment combined with a form of physical therapy and psychological support does not lead to improvement, nerve blocks and rehabilitation can be considered. Appropriately screened patients with persistent incapacitating pain may respond to neuromodulation. A specific form of this technique - spinal cord stimulation - delivers electric pulses via an implanted electrode connected to a battery in the epidural space around the spinal cord. We describe three patients, two of whom had persistent leg pain after disc surgery. The third patient suffered from diabetic neuropathy. Despite thorough pre-procedural screening by an anaesthetist-pain specialist, psychologist, physical therapist and specialised nurse, spinal cord stimulation failed in one patient. Psycho-social factors, inadequate coping skills and depression may lead to inadequate improvement and failure of this therapy.


Laparoscopic liver resections for hepatocellular carcinoma. Is it a feasible option for patients with liver cirrhosis?
Laparoscopic surgery has gained growing acceptance, but this does not hold for laparoscopic surgery of the liver, above all for patients with hepatocellular carcinoma (HCC) and cirrhosis. This approach mainly includes diagnostic procedures and interstitial therapies. However, we believe there is room for laparoscopic liver resections in well-selected cases. The aim of this study is to assess: (a) the risk of intraoperative bleeding and postoperative complications, (b) the safety and the respect of oncological criteria, and (c) the potential benefit of laparoscopic ultrasound in guiding liver resection. A prospective study of laparoscopic liver resections for hepatocellular carcinoma was undertaken in patients with compensated cirrhosis. Hepatic involvement had to be limited and located in the left or peripheral right segments (segments 2-6), and the tumor had to be 5 cm or smaller. Tumor location and its transection margins were defined by laparoscopic ultrasound. From January 1997, 22 out of 250 patients with HCC (9%) underwent laparoscopic liver resections. The mean patient age was 61.4 years (range, 50-79 years). In three patients, conversion to laparotomy was necessary. The laparoscopic resections included five bisegmentectoies (2 and 3), nine segmentectomies, two subsegmentectomies and three nonanatomical resections for extrahepatic growing lesions. The mean operative time, including laparoscopic ultrasonography, was 199 +/- 69 min (median, 220; range, 80-300). Perioperative blood loss was 183 +/- 72 ml (median, 160; range, 80-400 ml). There was no mortality. Postoperative complications occurred in two out of 19 patients: an abdominal wall hematoma occurred in one patient and a bleeding from a trocar access in the other patient requiring a laparoscopic re-exploration. Mean hospital stay of the whole series was 6.5 +/- 4.3 days (median, 5; range, 4-25), while the mean hospital stay of the 19 laparoscopic patients was 5.4 +/- 1 (median, 5; range, 4-8). Laparoscopic treatment should be considered in selected patients with HCC and liver cirrhosis in the left lobe or segments 5 and 6 of the liver. It is clear that certain types of laparoscopic resection are feasible and safe when carried out by adequately skilled surgeons with appropriate instruments.


Frontal Cortex Transcriptome Analysis of Mice Exposed to Electronic Cigarettes During Early Life Stages.
Electronic cigarettes (e-cigarettes), battery-powered devices containing nicotine, glycerin, propylene glycol, flavorings, and other substances, are increasing in popularity. They pose a potential threat to the developing brain, as nicotine is a known neurotoxicant. We hypothesized that exposure to e-cigarettes during early life stages induce changes in central nervous system (CNS) transcriptome associated with adverse neurobiological outcomes and long-term disease states. To test the hypothesis, pregnant C57BL/6 mice were exposed daily (via whole body inhalation) throughout gestation (3 h/day; 5 days/week) to aerosols produced from e-cigarettes either with nicotine (13-16 mg/mL) or without nicotine; following birth, pups and dams were exposed together to e-cigarette aerosols throughout lactation beginning at postnatal day (PND) 4-6 and using the same exposure conditions employed during gestational exposure. Following exposure, frontal cortex recovered from ~one-month-old male and female offspring were excised and analyzed for gene expression by RNA Sequencing (RNA-Seq). Comparisons between the treatment groups revealed that e-cigarette constituents other than nicotine might be partly responsible for the observed biological effects. Transcriptome alterations in both offspring sexes and treatment groups were all significantly associated with downstream adverse neurobiological outcomes. Results from this study demonstrate that e-cigarette exposure during early life alters CNS development potentially leading to chronic neuropathology.


[Auditory analysis of the sound source approaching and withdrawing: psychoacoustic and neurophysiological correlates].
The findings seemed to be based on direction and velocity of modelling the radial sound source shifting in free acoustic field. The threshold and the optimal parameters of the acoustic model imitating the approaching and withdrawing of the sound source shifting in silence and under conditions of noise, were established. A correlation between peak-to-peak amplitudes of the N1-P2 components of auditory EPs and the imitated direction of the sound shifting, was shown. The role of different left and right hemispheres' areas in perception of the radial sound source was analysed. The detector features of the central auditory neurones were shown as a possible mechanism of estimating the sound source approaching and withdrawal.


Striatal and white matter predictors of estimated diagnosis for Huntington disease.
Previous MRI studies with participants prior to manifest Huntington disease have been conducted in small single-site samples. The current study reports data from a systematic multi-national study during the prodromal period of Huntington disease and examines whether various brain structures make unique predictions about the proximity to manifest disease. MRI scans were acquired from 657 participants enrolled at 1 of 32 PREDICT-HD research sites. Only prodromal Huntington disease participants (those not meeting motor criteria for diagnosis) were included and subgrouped by estimated diagnosis proximity (Near, Mid, and Far) based upon a formula incorporating age and CAG-repeat length. Results show volumes of all three subgroups differed significantly from Controls for total brain tissue, cerebral spinal fluid, white matter, cortical gray matter, thalamus, caudate, and putamen. Total striatal volume demonstrated the largest differences between Controls and all three prodromal subgroups. Cerebral white matter offered additional independent power in the prediction of estimated proximity to diagnosis. In conclusion, this large cross-sectional study shows that changes in brain volume are detectable years to decades prior to estimated motor diagnosis of Huntington disease. This suggests that a clinical trial of a putative neuroprotective agent could begin as much as 15 years prior to estimated motor diagnosis in a cohort of persons at risk for but not meeting clinical motor diagnostic criteria for Huntington disease, and that neuroimaging (striatal and white matter volumes) may be among the best predictors of diagnosis proximity.


Individual patient risk stratification of high-risk neuroblastomas using a two-gene score suited for clinical use.
Several gene expression-based prognostic signatures have been described in neuroblastoma, but none have successfully been applied in the clinic. Here we have developed a clinically applicable prognostic gene signature, both with regards to number of genes and analysis platform. Importantly, it does not require comparison between patients and is applicable amongst high-risk patients. The signature is based on a two-gene score (R-score) with prognostic power in high-stage tumours (stage 4 and/or MYCN-amplified diagnosed after 18 months of age). QPCR-based and array-based analyses of matched cDNAs confirmed cross platform (array-qPCR) transferability. We also defined a fixed cut-off value identifying prognostically differing subsets of high-risk patients on an individual patient basis. This gene expression signature independently contributes to the current neuroblastoma classification system, and if prospectively validated could provide further stratification of high-risk patients, and potential upfront identification of a group of patients that are in need of new/additional treatment regimens.


A new classification for crown fractures of teeth.
The aim of this work is to define a classification for traumatic injuries to crowns of teeth that offers a simplified interpretation, which can be communicated easily. These data will help us to evaluate the future restorations (composite resins, crowns, porcelain veneers) according to the variable design and extension of initial crown fracture lines. For this reason we conducted research on a vast sample of subjects, who presented different traumatic lesions, in order to obtain a specific selection of these typologies of injuries. We reviewed the literature for a complete, brief classification of simple use, which could serve our cause. The traditional classifications (Andreasen, Ellis, OMS) did not satisfy us for different reasons. In fact, they only consider the initial lesion situation, never focusing on the shape of the lesion and therefore never giving suggestions for the best kind of material for restoration. On the contrary, our interest is to define the kind of more valid materials according to the variable design of crown fracture lines, to foresee the duration of these materials and the best time to substitute them. To simplify and make our research a more affordable one, we created a 4 classes classification (A-B-C-D) and 3 subclasses (b1-c1-d1). Class A: all the simple enamel lesions which involve a mesial or distal crown angle, or only the incisal edge; Class B: all the enamel-dentin lesions, which involve a mesial or distal crown angle and the incisal edge. When a pulpal exposure exists we define it a Subclass b1; Class C: all the enamel-dentin lesions, which involve the incisal edge and at least a third of the crown surface. When a pulp exposure exists we define it a Subclass c1. Class D: all the enamel-dentin lesions, which involve a mesial or distal crown angle and the incisal or palatal surface, with root cement involvement (crown-root fractures). When a pulpal exposure exists we define it a Subclass d1. This classification showed how different kinds of lesions (Class B, b1, C and c1, in our new classification) fall under the same definition (enamel-dentinal fractures) in traditional classifications (Andreasen, Ellis). However, they need a wholly different clinical approach, and the material involved in the treatment shows different behavior and duration. This new classification simplified the gathering of data and the communication among practitioners, thus confirming its importance in getting optimal diagnostic and therapeutic protocols. It also allowed us to identify the most frequent crown fractures (Class B, b1 and C, c1) that in our sample of patients (age range: 8-18) are typically treated with composite resins or original fragment reattachment technique. All these studies brought us to develop this new "easy to use" classification of dental crown lesions that helped us to gather data easily, to choose the right materials to improve the communication among practitioners including by electronic means,


Remarkable response to nivolumab in sarcomatoid malignant pleural mesothelioma with high PD-L1.
We report herein a case of sarcomatoid malignant pleural mesothelioma (MPM) with high PD-L1 expression who was refractory to standard chemotherapy but had a remarkable and sustained response to nivolumab. A 78-year-old man presented with right chest pain. Computed tomography (CT) showed a solid mass extending to the right pleura. Histopathological examination revealed the proliferation of spindle to pleomorphic ovoid shaped tumour cells, which are positive for calretinin and podoplanin. The patient was diagnosed with sarcomatoid MPM. Despite treatment with carboplatin and pemetrexed, the primary lesion rapidly progressed and new multiple pleural metastases were observed. Although his performance status decreased with advancing of symptoms and adverse events, nivolumab was administered. After the nivolumab treatment, CT showed a significant reduction in pleural tumours with a marked improvement in symptoms. In the primary specimens, TPS of PD-L1 was 80%. The patient has continued this treatment with sustained and remarkable effectiveness with good quality of life (QOL).


Endohyphal bacterium enhances production of indole-3-acetic acid by a foliar fungal endophyte.
Numerous plant pathogens, rhizosphere symbionts, and endophytic bacteria and yeasts produce the important phytohormone indole-3-acetic acid (IAA), often with profound effects on host plants. However, to date IAA production has not been documented among foliar endophytes -- the diverse guild of primarily filamentous Ascomycota that live within healthy, above-ground tissues of all plant species studied thus far. Recently bacteria that live within hyphae of endophytes (endohyphal bacteria) have been detected, but their effects have not been studied previously. Here we show not only that IAA is produced in vitro by a foliar endophyte (here identified as Pestalotiopsis aff. neglecta, Xylariales), but that IAA production is enhanced significantly when the endophyte hosts an endohyphal bacterium (here identified as Luteibacter sp., Xanthomonadales). Both the endophyte and the endophyte/bacterium complex appear to rely on an L-tryptophan dependent pathway for IAA synthesis. The bacterium can be isolated from the fungus when the symbiotic complex is cultivated at 36°C. In pure culture the bacterium does not produce IAA. Culture filtrate from the endophyte-bacterium complex significantly enhances growth of tomato in vitro relative to controls and to filtrate from the endophyte alone. Together these results speak to a facultative symbiosis between an endophyte and endohyphal bacterium that strongly influences IAA production, providing a new framework in which to explore endophyte-plant interactions.


Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription.
Stimulation of quiescent 3T3 cells with purified growth factors or of the pheochromocytoma cell line PC12 with nerve growth factor results in the rapid transient induction of c-fos, c-myc, and actin gene transcription (M.E. Greenberg and E.B. Ziff, Nature [London] 312:711-716; M.E. Greenberg, L.A. Greene, and E.B. Ziff, J. Biol. Chem. 26:14101-14110). We used protein synthesis inhibitors to investigate whether synthesis of new proteins plays a role in the rapid induction and subsequent repression of the transcription of these genes. Pretreatment of quiescent 3T3 cells with the inhibitor anisomycin before growth factor stimulation caused a superinduction of c-fos and c-myc mRNA levels upon growth factor addition. Nuclear runoff transcription analyses of 3T3 cells indicated that anisomycin potentiated c-fos, c-myc, and also actin expression at the transcriptional level, possibly by inhibiting transcriptional repression. Somewhat different results were obtained when PC12 cells were incubated with either anisomycin or cycloheximide. In PC12 cells protein synthesis inhibitors superinduced nerve growth factor activation of c-fos mRNA production but completely abolished the activation of c-myc. The results suggest that in PC12 cells c-fos transcription is activated by a protein-synthesis-independent mechanism, whereas c-myc stimulation requires new protein synthesis. The difference in the effect of anisomycin on growth factor activation of c-myc expression in 3T3 versus PC12 cells may be due to differential stringency of protein synthesis inhibition in the two cells or could reflect cell type differences in c-myc regulation.


A Printed Multicomponent Paper Sensor for Bacterial Detection.
We present a simple all-in-one paper-based sensor for E. coli detection using a composite ink made of a fluorogenic DNAzyme probe for bacterial recognition and signal generation, lysozyme that lyses whole bacterial cells, and pullulan/trehalose sugars that stabilize printed bioactive molecules. The paper sensor is capable of producing a fluorescence signal as a readout within 5 minutes upon contacting E. coli, can achieve a limit of detection of 100 cells/mL, in a variety of sample matrixes, without sample enrichment, and remains stable for at least 6 months when stored at ambient temperature. Therefore, this simple paper sensor provides rapid bacterial testing on site, and can be shipped and stored under ambient conditions to benefit users living in resource-limited regions.


Randomized Prospective Study of the Use of Anti-Inflammatory Drops After Selective Laser Trabeculoplasty.
Evaluating the use of Indomethacin, Dexamethasone, and no anti-inflammatory treatment immediately after selective laser trabeculoplasty (SLT). Prospective randomized clinical trial of 132 eyes. Both eyes of the patient underwent SLT. One of the eyes was treated with Indomethacin 0.1% or Dexamethasone 0.1% 3 times daily for 1 week; the other eye did not receive any anti-inflammatory treatment. Intraocular pressure (IOP) and inflammatory parameters were recorded at 1 hour, 1 week, 1, 3, and 6 months. Cells in the anterior chamber were present in 57% to 71% of the patients after 1 hour. About 16% to 37% of the patients reported pain/discomfort after 1 hour. Redness was present before SLT in 29% to 34% of the patients, probably due to antiglaucoma medication. After 1 hour, the amount of redness recorded raised to 32% to 42%, but the amount of patients with redness returned to pretreatment levels after 1 week. An IOP peak of >5 mm Hg above baseline IOP 1 hour after laser was present in 3% to 9% of the patients. IOP lowered 11% to 21% compared with IOP at baseline. The number of medications needed changed from 1.45 to 1.49 before, to 0.23 to 0.45 six months after SLT.No differential effects based on the kind of anti-inflammatory treatment or no treatment were found for any of the parameters. SLT induces little inflammation: anti-inflammatory drops do not make a significant difference in pain, redness, cells in anterior chamber, or peak IOP following SLT.The IOP-lowering effect of the SLT is not influenced by the use of Indomethacin or Dexamethasone.


Isolation and Characterization of Chi-like Salmonella Bacteriophages Infecting Two Salmonella enterica Serovars, Typhimurium and Enteritidis
Salmonella enterica Serovar Typhimurium and Salmonella enterica Serovar Enteritidis are well-known pathogens that cause foodborne diseases in humans. The emergence of antibiotic-resistant Salmonella serovars has caused serious public health problems worldwide. In this study, two lysogenic phages, STP11 and SEP13, were isolated from a wastewater treatment plant in Jeddah, KSA. Transmission electron microscopic images revealed that both phages are new members of the genus "Chivirus" within the family Siphoviridae. Both STP11 and SEP13 had a lysis time of 90 min with burst sizes of 176 and 170 PFU/cell, respectively. The two phages were thermostable (0 °C ≤ temperature < 70 °C) and pH tolerant at 3 ≤ pH < 11. STP11 showed lytic activity for approximately 42.8% (n = 6), while SEP13 showed against 35.7% (n = 5) of the tested bacterial strains. STP11 and STP13 have linear dsDNA genomes consisting of 58,890 bp and 58,893 bp nucleotide sequences with G + C contents of 57% and 56.5%, respectively. Bioinformatics analysis revealed that the genomes of phages STP11 and SEP13 contained 70 and 71 ORFs, respectively. No gene encoding tRNA was detected in their genome. Of the 70 putative ORFs of phage STP11, 27 (38.6%) were assigned to functional genes and 43 (61.4%) were annotated as hypothetical proteins. Similarly, 29 (40.8%) of the 71 putative ORFs of phage SEP13 were annotated as functional genes, whereas the remaining 42 (59.2%) were assigned as nonfunctional proteins. Phylogenetic analysis of the whole genome sequence demonstrated that the isolated phages are closely related to Chi-like Salmonella viruses.


Patient-reported outcome measures in pediatric palliative care-a protocol for a scoping review.
In pediatric palliative care (PPC), there is a need to involve the child's voice in situations regarding their symptoms and care needs. Patient-reported outcome measures (PROMs) can be tools to systematically gather data reported from the child or a proxy if the child is not capable to self-report in order to provide the services they need. There has been a rapid development in PROM research the last decade, and there is a need for an overview of current knowledge and experiences in the field. Thus, we aim to explore and summarize what is known from the published research about PROMs in PPC. We propose a scoping review following the framework by Arksey and O'Malley and the PRISMA Extension for Scoping Reviews checklist. A systematic search will be performed in the following databases: Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), American Psychological Association (APA) PsycInfo, Health and Psychosocial Instruments (HaPI), and Allied and Complementary Medicine Database (AMED). The search will be followed by snowballing to identify key papers and significant researchers for additional citations. Covidence will facilitate the independent review of eligible citations, and data will be extracted and presented descriptively, and thematically analyzed using NVivo. The scoping review suggested in this protocol will identify PROMs which have been proposed in PPC and clarify the experiences with their use. The findings of this review will be relevant for researchers and healthcare personnel caring for children and adolescents in PPC. In addition, by highlighting knowledge gaps about the use of PROMs in PPC, this review will point out future needs within this field of research, which is crucial for improving quality of care in PPC. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/yfch2/ .


An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells.
Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.


Transcript expression of the freeze responsive gene fr10 in Rana sylvatica during freezing, anoxia, dehydration, and development.
Freeze tolerance is a critical winter survival strategy for the wood frog, Rana sylvatica. In response to freezing, a number of genes are upregulated to facilitate the survival response. This includes fr10, a novel freeze-responsive gene first identified in R. sylvatica. This study analyzes the transcriptional expression of fr10 in seven tissues in response to freezing, anoxia, and dehydration stress, and throughout the Gosner stages of tadpole development. Transcription of fr10 increased overall in response to 24 h of freezing, with significant increases in expression detected in testes, heart, brain, and lung when compared to control tissues. When exposed to anoxia; heart, lung, and kidney tissues experienced a significant increase, while the transcription of fr10 in response to 40% dehydration was found to significantly increase in both heart and brain tissues. An analysis of the transcription of fr10 throughout the development of the wood frog showed a relatively constant expression; with slightly lower transcription levels observed in two of the seven Gosner stages. Based on these results, it is predicted that fr10 has multiple roles depending on the needs and stresses experienced by the wood frog. It has conclusively been shown to act as a cryoprotectant, with possible additional roles in anoxia, dehydration, and development. In the future, it is hoped that further knowledge of the mechanism of action of FR10 will allow for increased stress tolerance in human cells and tissues.


Investigational drugs for the treatment of spinal cord injury: review of preclinical studies and evaluation of clinical trials from Phase I to II.
Efforts in basic research have clarified mechanisms involved in spinal cord injury (SCI), and resulted in positive findings using experimental treatments including cell transplantation and drug administration preclinically. Based on accumulated results, various clinical trials have begun for human SCI. In this review, the authors focus on five investigational drugs: riluzole, minocycline, Rho protein antagonist, magnesium chloride in polyethylene glycol formulation, and basic fibroblast growth factor. All drugs have established safety and tolerability from Phase I clinical trials, and are now in Phase II. They have been proven to have neuroprotective and/or neuroregenerative effects in animal models of SCI. To date, diverse drugs have been translated into clinical trials, but none have reached clinical application. A key gap was the lack of reliable biomarkers for SCI to fast-track Phase I/II trials. Furthermore, problems were often due to lack of adequate outcome assessments for both animal models and SCI patients. In order to advance clinical trials more quickly and with greater success, more clinically relevant animal models should be used in basic research. Clinically, it is indispensable to use appropriate outcome measurements and to construct a wide network among clinical centers to validate the efficacy of drugs.


Evidence for shared susceptibility in bipolar disorder and schizophrenia.
This article reviews evidence that bipolar disorder (BPD) and schizophrenia (SZ) share familial risk characteristics. The topic is introduced with a brief discussion of various shared epidemiologic characteristics of SZ and BPD. Family studies of BPD and SZ, conducted by multiple independent groups of investigators, are consistent with partial overlap in familial susceptibility. Given that the family study data suggest overlap in familial susceptibility for BPD and SZ, several confirmed linkages of BPD or SZ are reviewed, with the conclusion that there are five genomic regions for which evidence suggests shared genetic susceptibility of BPD and SZ. It is suggested that nosology must be changed to reflect the genetic origins of the multiple disorders that are collectively described by the terms BPD and SZ.


Acoustooptic characterization of a birefringent two-mode photonic crystal fiber.
The effect of axial variations in acoustooptic phase-mismatch coefficient of a two-mode birefringent photonic crystal fiber (PCF) is studied experimentally using two different methods. The first method is to determine axial non-uniformities directly from the transmission spectrum, while the second method is to use acoustic pulses. Both methods are seen to be in good agreement. It is found that axial non-uniformities increase the coupling bandwidth significantly as compared to an axially uniform fiber. The effect of acoustic birefringence is also considered.


Serum high-density lipoprotein cholesterol and breast cancer risk by menopausal status, body mass index, and hormonal receptor in Korea.
High-density lipoprotein cholesterol (HDL-C) has been suggested to be associated with breast cancer. However, the roles of HDL-C and hypertriglyceridemia on breast cancer still have been controversial. The goal of this study was to investigate the association between HDL-C with breast cancer risk, stratifying by menopausal status, and body mass index. The hormonal receptor status of breast has been proposed to modify the effect of HDL-C on breast cancer. Multicenter hospital-based case-control study was conducted from November 2004 to December 2005 in Korea. After one to two individual matchings by age (+/-5 years) and menopausal status, 690 cases and 1,380 controls were included in the analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by conditional, unconditional, and multinomial logistic regressions. Protective effect of HDL-C on breast cancer was only observed among premenopausal women with an OR (95% CI) of 0.49 (0.33-0.72) for HDL-C > or = 60 versus <50 mg/dL (P(trend) < 0.01). Only nonobese premenopausal women had a significant decreased risk (OR, 0.34; 95% CI, 0.22-0.53). OR (95% CI) of low HDL-C (<50 mg/dL) and high triglyceride (TG; > or = 150 mg/dL) category was 2.20 (1.32-3.67) on estrogen receptor-negative and progesterone receptor-negative breast cancer compared with high HDL-C (> or = 50 mg/dL) and low TG (<150 mg/dL) category. This study suggests that higher level of HDL-C may reduce breast cancer risk among premenopausal women. Estrogen receptor-negative and progesterone receptor-negative breast cancer was associated with dyslipidemia, which implicates that association among HDL-C, TG, and breast cancer may be modified by receptor status.


Organochlorine pesticides and polychlorinated biphenyls in sewage sludge from Egypt.
The purpose of this study was to determine the levels, distribution and toxicological potential of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in sewage sludge samples from several WWTPs in the Alexandria area, Egypt. The POPs of interest were 26 PCBs and 16 OCPs. Analyses were performed by gas chromatography with electron impact mass spectrometric detection in the selected ion monitoring mode (GC-MS-SIM) using deuterated organochlorines as internal standards. Total concentrations of OCPs and Σ7 PCBs (ICES) in sludge ranged from 44.2 to 489 μg/kg dw. and 5,600 to 11,000 μg/kg dw., respectively. The highest concentration levels were found for PCBs, HCHs, DDTs, and HCB, in this order. The PCB homologue profiles in sludge samples were dominated by penta- and hexa-chlorinated biphenyls. Seasonal variations were observed for OCPs with higher levels in summer, which reflects more usage in warmer climates. Composite profiles of OCP metabolites indicated new inputs of lindane and technical endosulfan and earlier usage of DDT and technical chlordane. Contamination levels of OCPs and PCBs for Egyptian sludge can be categorized as moderate to high compared to other countries worldwide. The OCP content in none of the samples exceeded limits set by the European Commission for use of sludge in agriculture; while all the concentrations of PCBs in sludge samples were higher by one order of magnitude than the upper limit for land application.


Human eosinophils recognize endogenous danger signal crystalline uric acid and produce proinflammatory cytokines mediated by autocrine ATP.
Eosinophils are multifunctional leukocytes involved in various inflammatory processes, as well as tissue remodeling and immunoregulation. During inflammation and infection, injured cells and damaged tissues release uric acid and monosodium urate (MSU) crystals as important endogenous danger signals. Uric acid is also implicated in the immunogenic effects of an authentic Th2 adjuvant, aluminum hydroxide. Eosinophils often localize at sites of Th2-type chronic inflammation; therefore, we hypothesized that eosinophils may react to endogenous danger signals. We found that human eosinophils migrate toward soluble uric acid and MSU crystals in a gradient-dependent manner. Eosinophils incubated with MSU crystals, but not those incubated with uric acid solution, produced elevated levels of IL-6 and IL-8/CXCL8. Other cytokines and chemokines, including IL-1beta, IL-10, IL-17, IFN-gamma, CCL2, CCL3, CCL4, TNF-alpha, G-CSF, GM-CSF, fibroblast growth factor, vascular endothelial growth factor, and TGF-beta, were also produced by eosinophils incubated with MSU crystals. Eosinophils exposed to MSU crystals rapidly (i.e., within 1 min of exposure) released ATP into the extracellular milieu. Importantly, this autocrine ATP was necessary for eosinophils to produce cytokines in response to MSU crystals, and P2 nucleotide receptors, in particular P2Y(2), are likely involved in this positive feedback loop. Finally, at higher concentrations, MSU crystals promoted P2R-dependent release of a granule protein (eosinophil-derived neurotoxin) and cell death. Thus, human eosinophils may respond to particulate damage-associated endogenous danger signals. These responses by eosinophils to tissue damage may explain the self-perpetuating nature of chronic inflammation in certain human diseases, such as asthma.


Combined swimming and soybean intake reduce early atherosclerotic lesions and serum oxidative stress in mice.
Physical exercise and soybean intake reduced oxidative stress and atherosclerosis. However, the associated effects of both interventions have not been yet investigated. Thus, we aimed to evaluate the combined effects of swimming and soybean intake on lipid profile, oxidative stress and atherogenesis. Ten-week-old male Low-Density Lipoprotein Receptor Knockout mice were divided into 4 groups (N.=8 for each group): control diet without swimming; control diet with swimming; soybean rich diet without swimming and soybean rich diet with swimming. Diets were based on American Institute of Nutrition 93 Growth. The diet of soybean groups was made by soybean extract contained isoflavones. The animals in the exercise groups underwent a 6-week swimming program five times per week. Plasma lipid profile was determined using enzymatic kits. Oxidative stress was measured by thiobarbituric acid reactive substances, hydroperoxide and the lipid oxidation resistance determinations. Atherosclerotic lesions were calculated by morphometry. Soybean intake increased high density lipoprotein cholesterol. Moreover, soybean and exercise individually reduced hepatic oxidative stress and atherogenesis in aortic valve. No additional effect was seen in soybean+exercise group. However, the association of soybean and exercise reduced the percentage of lesion area in arch, thoracic and abdominal aorta and increased serum antioxidant potential. Soybean intake and swimming are beneficial in reducing atherosclerosis besides improving lipid profile and reducing lipid peroxidation. The association of soybean and swimming aggregates beneficial effects in serum antioxidant potential and in aorta lesion.


Towards a better understanding of solid dispersions in aqueous environment by a fluorescence quenching approach.
Solid dispersions (SDs) represent an important formulation technique to achieve supersaturation in gastro-intestinal fluids and to enhance absorption of poorly water-soluble drugs. Extensive research was leading to a rather good understanding of SDs in the dry state, whereas the complex interactions in aqueous medium are still challenging to analyze. This paper introduces a fluorescence quenching approach together with size-exclusion chromatography to study drug and polymer interactions that emerge from SDs release testing in aqueous colloidal phase. Celecoxib was used as a model drug as it is poorly water-soluble and also exhibits native fluorescence so that quenching experiments were enabled. Different pharmaceutical polymers were evaluated by the (modified) Stern-Volmer model, which was complemented by further bulk analytics. Drug accessibility by the quencher and its affinity to celecoxib were studied in physical mixtures as well as with in SDs. The obtained differences enabled important molecular insights into the different formulations. Knowledge of relevant drug-polymer interactions and the amount of drug embedded into polymer aggregates in the aqueous phase is of high relevance for understanding of SD performance. The novel fluorescence quenching approach is highly promising for future research and it can provide guidance in early formulation development of native fluorescent compounds.


Anti-obesity activity of anthocyanin and carotenoid extracts from color-fleshed sweet potatoes.
The anti-obesity effects of anthocyanin and carotenoid extracts from color-fleshed potatoes were studied with 3T3-L1 cells in vitro and high-fat diet (HFD)-induced obese mice in vivo. Treatment of 3T3-L1 adipocytes with anthocyanin and carotenoid extracts, respectively, after differentiation induction significantly inhibited fat accumulation by 63.1 and 83.5%. Studies of adipogenesis inhibition showed that the anthocyanin extract acts at intermediate stages, whereas the carotenoid extract influences all the stages. The extracts significantly diminished triglyceride (TG) content and peroxisome proliferator-activated receptor gamma (PPARγ) protein expression during adipogenesis of the intermediate stage. Oral administration of anthocyanin and carotenoid extracts, respectively, to HFD-fed mice significantly reduced weight gain and restored TG levels to normal or lower as compared to the HFD-fed group with improvement of a lipid profile, TG to HDL-C ratio. Histological differences in liver tissues revealed that the extracts protected the liver tissue from adipogenesis by HFD fed. This research presents the first direct demonstration that the two pigment extracts from sweet potato exhibit anti-obesity activities. PRACTICAL APPLICATIONS: Anthocyanins and carotenoids are the main pigments of purple- and orange-fleshed sweet potatoes, respectively, which are highly nutritious foods with antidiabetic and antioxidant properties. Obesity is a rapidly growing health problem that increases major risk factors of several serious diseases including cardiovascular diseases, diabetes, and cancer. The results of this research suggest that anthocyanin and carotenoid-rich extracts from color-fleshed sweet potatoes may be useful as supplementary ingredients for the treatment of obesity and related diseases.


Respiratory Inflammation and Short-Term Ambient Air Pollution Exposures in Adult Beijing Residents with and without Prediabetes: A Panel Study.
Accumulating evidence suggests that individuals with glucose metabolism disorders are susceptible to mortality associated with fine particles. However, the mechanisms remain largely unknown. We examined whether particle-associated respiratory inflammation differed between individuals with prediabetes and healthy control participants. Based on a panel study [A prospective Study COmparing the cardiometabolic and respiratory effects of air Pollution Exposure on healthy and prediabetic individuals (SCOPE)] conducted in Beijing between August 2013 and February 2015, fractional exhaled nitric oxide (FeNO) was measured from 112 participants at two to seven visits to indicate respiratory inflammation. Particulate pollutants-including particulate matter with an aerodynamic diameter of ≤2.5μm (PM2.5), black carbon (BC), ultrafine particles (UFPs), and accumulated-mode particles-were monitored continuously at a single central monitoring site. Linear mixed-effects models were used to estimate associations between ln-FeNO with pollutant concentrations at individual 1-h lags (up to 24 h) and with average concentrations at 8 and 24 h before the clinical visit. We evaluated glucose metabolism disorders as a potential modifier by comparing associations between participants with high vs. low average fasting blood glucose (FBG) and homeostasis model assessment insulin resistance (HOMA-IR) levels. FeNO was positively associated with all pollutants, with the strongest associations for an interquartile range increase in 1-h lagged exposures (ranging from 21.3% for PM2.5 to 74.7% for BC). Associations differed significantly according to average HOMA-IR values when lagged 6-18 h for PM2.5, 15-19 h for BC, and 6-15 h for UFPs, with positive associations among those with HOMA-IR≥1.6 while associations were closer to the null or inverse among those with HOMA-IR<1.6. Associations between PM2.5 and FeNO were consistently higher among individuals with average FBG≥6.1 mmol/L vs. low FBG, with significant differences for multiple hourly lags. Glucose metabolism disorders may aggravate respiratory inflammation following exposure to ambient particulate matter. https://doi.org/10.1289/EHP4906.


[AGIKO (Clinical Research Fellow); a training model aimed at enhancement of clinical scientific research].
The enhancement of clinical scientific research in the Netherlands is being stimulated to a substantial extent by the introduction and stimulation of a training model aimed at the combined training of physicians to both a general practitioner or specialist and a clinical researcher, the AGIKO (Clinical Research Fellow). The model has been recognized by the Central College for Recognition and Registration of Medical Specialists. Extra stimulation by the section Medical Sciences of the Netherlands Organization for Scientific Research (MW-NWO) makes it possible to appoint AGIKOs on second or third flows of funds but also within the first flow of funds. During the last two years, 25 AGIKO applications from ten medical specialisms have been approved. The AGIKO model may help to meet (expected) needs for future clinical-medical research workers in specific research areas.


Cost-effectiveness of antihypertensive treatment in patients 80 years of age or older in Switzerland: an analysis of the HYVET study from a Swiss perspective.
This analysis shows the economic benefit of antihypertensive treatment in patients 80 years of age or older from the perspective of the Swiss healthcare system. The cost-effectiveness analysis of antihypertensive treatment in the elderly was carried out applying the results of the Hypertension in the Very Elderly Trial study to the Swiss healthcare system. The analysis shows that hypertension treatment provides, compared with placebo, an additional life expectancy of 0.0457 years per patient, over a follow-up period of 2 years. The medication cost was covered by the reduction of costs related to the treatment of strokes, myocardial infarctions and heart failure: the total cost per patient in the active group resulted in a dominant strategy of savings compared with the placebo group. Sensitivity analysis yielded a stable estimate after varying the costs of medication, stroke, myocardial infarction, heart failure and life expectancy, confirming the robustness of these results. Moreover, considering that antihypertensive treatment also positively affects the incidence of dementia, those net benefits might even be underestimated.


Exploring the potential for introducing home monitoring of blood pressure during pregnancy into maternity care: current views and experiences of staff-a qualitative study.
One in 20 women are affected by pre-eclampsia, a major cause of maternal and perinatal morbidity, death and premature birth worldwide. Diagnosis is made from monitoring blood pressure (BP) and urine and symptoms at antenatal visits after 20 weeks of pregnancy. There are no randomised data from contemporary trials to guide the efficacy of self-monitoring of BP (SMBP) in pregnancy. We explored the perspectives of maternity staff to understand the context and health system challenges to introducing and implementing SMBP in maternity care, ahead of undertaking a trial. Exploratory study using a qualitative approach. Eight hospitals, English National Health Service. Obstetricians, community and hospital midwives, pharmacists, trainee doctors (n=147). Semi-structured interviews with site research team members and clinicians, interviews and focus group discussions. Rapid content and thematic analysis undertaken. The main themes to emerge around SMBP include (1) different BP changes in pregnancy, (2) reliability and accuracy of BP monitoring, (3) anticipated impact of SMBP on women, (4) anticipated impact of SMBP on the antenatal care system, (5) caution, uncertainty and evidence, (6) concerns over action/inaction and patient safety. The potential impact of SMBP on maternity services is profound although nuanced. While introducing SMBP does not reduce the responsibility clinicians have for women's health, it may enhance the responsibilities and agency of pregnant women, and introduces a new set of relationships into maternity care. This is a new space for reconfiguration of roles, mutual expectations and the relationships between and responsibilities of healthcare providers and women. NCT03334149.


LIVE TULAREMIA VACCINE I. : Host-Parasite Relationship in Monkeys Vaccinated Intracutaneously or Aerogenically.
Eigelsbach, H. T. (Fort Detrick, Frederick, Md.), J. J. Tulis, M. H. McGavran and J. D. White. Live tularemia vaccine. I. Host-parasite relationship in monkeys vaccinated intracutaneously or aerogenically. J. Bacteriol. 84:1020-1027. 1962.-Bacteriological, histological, immunohistochemical, and serological studies were made on monkeys administered live tularemia vaccine strain LVS by either of two routes. Comparative data are presented on nonvaccinated monkeys exposed via the respiratory route to a highly virulent strain of Pasteurella tularensis. Tissue changes resulting from either aerogenic or intracutaneous vaccination were mild, and consisted primarily of the proliferation of histiocytes without the formation of granulomas. The vaccine strain was isolated from the site of vaccination of animals inoculated dermally, from the lungs of animals vaccinated aerogenically, and from the regional lymph nodes, liver, and spleen of both groups; it was not isolated from the blood or bone marrow. Proliferation of the vaccine strain at the site of dermal inoculation and in the lungs of animals exposed aerogenically was observed within 24 hr; in both groups, the maximal viable population was reached within 3 days and maintained through the 10th day. A reduction in the number of viable vaccine organisms had begun by the 14th day; isolations were obtained only from the regional lymph nodes on the 28th day, and the vaccine strain was not isolated from any of the tissues cultured on the 90th day. Because the monkey is less resistant to tularemia than is man, the benign response of this animal to live tularemia vaccine indicates that the vaccine might also be safe for man when administered by either the dermal or respiratory route.


[Bronchodilator efficacy of combined salmeterol and tiotropium in patients with chronic obstructive pulmonary disease].
Bronchodilators are still the most effective drugs for controlling the symptoms of chronic obstructive pulmonary disease (COPD). Tiotropium bromide, a long-acting anticholinergic drug, has recently been added to the therapeutic arsenal for the disease. To date, there have been no studies combining 2 long-acting bronchodilators. The aim of the present trial was to determine whether the combination of salmeterol and tiotropium improved lung function in COPD patients more than either of them alone. Twenty-two patients (20 men) diagnosed with COPD, with a mean age of 64 years, were enrolled in this cross-over trial. Active smokers were excluded. Mean (SD) forced expiratory volume in 1 second (FEV1) was 43% (14%) of predicted. All patients were experienced in the use of inhalers. The following 3 therapeutic combinations were randomly assigned to be administered for a 1-week period: a) fluticasone (500 microg/12 h), salmeterol (50 microg/12 h) and placebo; b) fluticasone, tiotropium (18 microg/24 h), and placebo; and c) fluticasone, salmeterol, and tiotropium. At the end of each period, forced spirometry was performed before inhalation of the therapeutic combination (between 8:30 am and 9:30 am) and 2 hours after inhalation. Throughout the week, morning peak flow rates measured immediately before inhalation were recorded, and there was a 48-hour wash-out period between each therapeutic combination. All the patients completed the protocol. There were no significant differences in preinhalation or postinhalation FEV1 with salmeterol compared to tiotropium (preinhalation FEV1, 1.17 [0.55] L compared to 1.19 [0.49] L; postinhalation FEV1, 1.32 [0.65] L compared to 1.29 [0.61] L). In all cases postinhalation FEV1 was significantly higher than preinhalation FEV1. The combination of fluticasone, salmeterol, and tiotropium proved superior to the other 2 combinations with respect to both preinhalation FEV1 and postinhalation FEV1 (preinhalation FEV1, 1.32 [0.56] L, [P<.03 in both comparisons]; postinhalation FEV1, 1.49 [0.68] L [P<.001 in both comparisons]). Peak flow rate was also significantly higher with the combination of the 2 bronchodilators (345 L/min compared to 291 L/min and 311 mL, respectively [P <.04 in both cases]). There were no notable side effects. In terms of improvement in lung function, the combination of salmeterol and tiotropium together with fluticasone is more effective in patients with moderate-to-severe COPD than either of the 2 bronchodilators administered alone.


Costs incurred by parents of very low birth weight infants after the initial neonatal hospitalization.
To assess the economic impact of the posthospitalization care of very low birth weight (VLBW) infants, the costs incurred in the first year of life by 32 VLBW infants were compared with those incurred by 34 term, comparison infants. Diaries and quarterly interviews revealed that VLBW infants averaged $10,139 in direct medical charges compared with $1179 for the term infants; the differential in charges was greatest in the first two quarters and virtually disappeared by the fourth quarter. In addition, expenditures associated with transportation and child care presented an added substantial burden, although only the former were significantly higher for the VLBW infants. Clinicians may need to inquire specifically about the burden on family resources because, despite the economic burden and evidence of less social support, the parents of VLBW infants were less likely to perceive their child's care as having an impact on the family than were the parents of term children.


Changes in cardiac output and cerebral oxygenation during prone and supine sleep positioning in healthy term infants.
To investigate the changes in systemic and cerebral haemodynamics between supine and prone sleep in healthy term infants during the early postnatal period. Healthy term infants without congenital anomalies, patent ductus arteriosus and/or small for gestational age status were enrolled. Infants were placed in supine (SP1), prone (PP) and back in supine (SP2) position for 15 min each while asleep. Cardiac output (CO) and stroke volume (SV) were assessed by electrical velocimetry (EV) and echocardiography (echo), and cerebral regional oxygen saturation (CrSO2) in the frontal lobes was monitored by near-infrared spectroscopy. Heart rate (HR) and SpO2 were continuously monitored by conventional monitoring. In 34 healthy term infants (mean age 3.7±1.2 days; 16 females), 66 sets of serial CO measurements (34 EV and 32 echo) in three sleep positions were obtained. Mean COEV and COecho were 182±57 (SP1), 170±50 (PP) and 177±54 (SP2), and 193±48 (SP1), 174±40 (PP) and 192±50 (SP2) mL/kg/min, respectively. Mean SVEV and SVecho were 1.46±0.47 (SP1), 1.36±0.38 (PP) and 1.37±0.39 (SP2), and 1.54±40 (SP1), 1.38±0.38 (PP) and 1.51±0.41 (SP2) mL/kg, respectively. Repeated measures analysis of variance revealed a decrease in CO and SV during prone positions by both EV and echo, while HR, SpO2 and CrSO2 did not change. Thirty-eight per cent of the CO measurements decreased≥10% during prone positioning. In healthy term infants, CO decreases in prone position due to a decrease in SV and not HR. CO recovers when placed back in supine. However, frontal lobe CrSO2 does not change in the different positions.


DNA accumulation on ventilation system filters in university buildings in Singapore.
Biological particles deposit on air handling system filters as they process air. This study reports and interprets abundance and diversity information regarding biomass accumulation on ordinarily used filters acquired from several locations in a university environment. DNA-based analysis was applied both to quantify (via DNA fluorometry and qPCR) and to characterize (via high-throughput sequencing) the microbial material on filters, which mainly processed recirculated indoor air. Results were interpreted in relation to building occupancy and ventilation system operational parameters. Based on accumulated biomass, average DNA concentrations per AHU filter surface area across nine indoor locations after twelve weeks of filter use were in the respective ranges 1.1 to 41 ng per cm2 for total DNA, 0.02 to 3.3 ng per cm2 for bacterial DNA and 0.2 to 2.0 ng DNA per cm2 for fungal DNA. The most abundant genera detected on the AHU filter samples were Clostridium, Streptophyta, Bacillus, Acinetobacter and Ktedonobacter for bacteria and Aspergillus, Cladosporium, Nigrospora, Rigidoporus and Lentinus for fungi. Conditional indoor airborne DNA concentrations (median (range)) were estimated to be 13 (2.6-107) pg/m3 for total DNA, 0.4 (0.05-8.4) pg/m3 for bacterial DNA and 2.3 (1.0-5.1) pg/m3 for fungal DNA. Conditional airborne concentrations and the relative abundances of selected groups of genera correlate well with occupancy level. Bacterial DNA was found to be more responsive than fungal DNA to differences in occupancy level and indoor environmental conditions.


Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study.
Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.


Changes in end-plate cholinesterase and axons during muscle degeneration and regeneration.
Injection of bupivacaine into the rat anterior tibial muscle produced rapid necrosis with disintegration of muscle fibres and phagocytic infiltration within two days. Regenerating myotubes appeared four days after injection, and muscle structure was restored seven days after injection. One day after injection, axons and end-plate cholinesterase appeared normal in spite of the underlying muscle fibre necrosis. Intensity of cholinesterase staining was gradually reduced through the second and third day but axons remained intact. On the fourth day, newly formed end-plates delineated by cholinesterase stain were seen on myotubes. Some were innervated by thin regenerating axons. Axonal outgrowth appeared to compensate for occasional neuronal degeneration and for the greater number of end-plates on myotubes. In some areas, not all end-plates were innervated by the fourth day but were by the fifth day. On the sixth and seventh day after myotube maturation, a process of degeneration of superfluous end-plates and axons occurred, reducing their number to the number of muscle fibres. Fourteen and 28 days after injection, the innervation pattern was normal except for a slight increase in terminal innervation band width. These results indicate that injection of bupivacaine does not directly affect intramuscular nerves and that the changes observed in this experimental model are the consequence of muscle fibre degeneration and regeneration.


Seismic Velocity and Density Jumps Across the 410- and 660-Kilometer Discontinuities.
The average seismic velocity and density jumps across the 410- and 660-kilometer discontinuities in the upper mantle were determined by modeling the observed range dependence in long-period seismic wave arrivals that reflect off of these interfaces. The preliminary reference Earth model (PREM) is within the computed 95 percent confidence ellipse for the 410-km discontinuity but outside the allowed jumps across the 660-kilometer discontinuity. Current pyrolite mantle models appear consistent with the constraints for the 410-kilometer discontinuity but overpredict amplitudes for the 660-kilometer reflections. The density jump across the 660-kilometer discontinuity is between 4 and 6 percent, below the PREM value of 9.3 percent commonly used in mantle convection calculations.