Positively-charged reduced graphene oxide as an adhesion promoter for preparing a highly-stable silver nanowire film.
An ultrathin conductive adhesion promoter using positively charged reduced graphene oxide (rGO-NH3(+)) has been demonstrated for preparing highly stable silver nanowire transparent conductive electrodes (AgNW TCEs). The adhesion promoter rGO-NH3(+), spray coated between the substrate and AgNWs, significantly enhances the chemical and mechanical stabilities of the AgNW TCEs. Besides, the ultrathin thickness of the rGO-NH3(+) ensures excellent optical transparency and mechanical flexibility for TCEs. The AgNW films prepared using the adhesion promoter are extremely stable under harsh conditions, including ultrasonication in a variety of solvents, 3M Scotch tape detachment test, mechanical bending up to 0.3% strain, or fatigue over 1000 cycles. The greatly enhanced adhesion force is attributed to the ionic interactions between the positively charged protonated amine groups in rGO-NH3(+) and the negatively charged hydroxo- and oxo-groups on the AgNWs. The positively charged GO-NH3(+) and commercial polycationic polymer (poly allylamine hydrochloride) are also prepared as adhesion promoters for comparison with rGO-NH3(+). Notably, the closely packed hexagonal atomic structure of rGO offers better barrier properties to water permeation and demonstrates promising utility in durable waterproof electronics. This work offers a simple method to prepare high-quality TCEs and is believed to have great potential application in flexible waterproof electronics.


Identifying and Transmitting the Culture of Emergency Medicine Through Simulation.
Simulation is commonly used in medical education. It offers the opportunity for participants to apply theoretical knowledge and practice nontechnical skills. We aimed to examine how simulation may also help to identify emergency medicine culture and serve as a tool to transmit values, beliefs, and practices to medical learners. We undertook a focused ethnography of a simulated emergency department exercise delivered to 98 third-year medical students. This ethnography included participant observation, informal interviews, and document review. Analysis was performed using a recursive method, a simultaneous deductive and inductive approach to data interpretation. All 20 staff (100%) and 92 of 98 medical students (94%) participated in the study. We identified seven core values-identifying and treating dangerous pathology, managing uncertainty, patients and families at the center of care, balancing needs and resources at the system level, value of the team approach, education as integral, and emergency medicine as part of self-identity-and 27 related beliefs that characterized emergency medicine culture. We observed that culture was transmitted during the simulation exercise. This study contributes to the characterization of the culture of emergency medicine by identifying core values and beliefs that are foundational to the specialty. Simulation facilitated cultural compression, which allowed for ready identification of values, beliefs, and practices and also facilitated transmission of culture to learners. This study expands understanding of the culture of emergency medicine and the role of simulation in the process of cultural exchange.


Expedited Partner Therapy (EPT) increases the frequency of partner notification among MSM in Lima, Peru: a pilot randomized controlled trial.
Expedited Partner Therapy (EPT) has been shown to improve treatment outcomes among heterosexual partners of individuals with curable sexually transmitted infections (STIs). Although the use of EPT with men who have sex with men (MSM) has been debated, due to the potential for missed opportunities to diagnose unidentified cases of HIV and syphilis infection in symptomatic partners, increases in partner notification (PN) resulting from use of EPT may promote testing and treatment of otherwise unidentified partners. We assessed the impact of EPT on self-reported PN among MSM in Peru with gonorrheal (GC) and/or chlamydial (CT) infection. We enrolled 173 MSM in Lima, Peru with symptomatic or asymptomatic GC and/or CT infection between 2012 and 2014. We enrolled 44 MSM with symptomatic urethritis/proctitis and 129 MSM with asymptomatic GC/CT infection, diagnosed based on nucleic acid testing (Aptima Combo 2 Transcription-Mediated Amplification [TMA]) from urethral, pharyngeal, and rectal sites. Eligible participants were randomly assigned to receive either standard PN counseling (n = 84) or counseling plus EPT (cefixime 400 mg/azithromycin 1 g) for up to five recent partners (n = 89). Self-reported notification was assessed by computer-assisted self-administered survey among 155 participants who returned for 14-day follow-up. The median age of participants was 26 (interquartile range [IQR]: 23-31) with a median of 3 sexual partners (IQR: 2-4) in the previous 30-day period. Among all participants, 111/155 (71.6%) notified at least one partner at 14-day follow-up with a median of 1 partner notified per participant (IQR: 0-2). For participants randomized to receive EPT, 69/83 (83.1%) reported notifying at least one partner, compared with 42/72 (58.3%) of participants in the control arm (odds ratio = 3.52; 95% confidence interval [CI]: 1.68-7.39). The proportion of all recent partners notified was significantly greater in the EPT than in the control arm (53.5%, 95% CI: 45.0-62.0% versus 36.4%, 95% CI: 27.0-47.4%). Provision of EPT led to significant increases in notification among Peruvian MSM diagnosed with GC/CT infection. Additional research is needed to assess the impact of EPT on biological outcomes, including persistent or recurrent infection, antimicrobial resistance, and HIV/STI transmission, in MSM sexual networks. ClinicalTrials.gov, NCT01720654 . Registered on 10/29/2012.


Constructing simple yet accurate potentials for describing the solvation of HCl/water clusters in bulk helium and nanodroplets.
The infrared spectroscopy of molecules, complexes, and molecular aggregates dissolved in superfluid helium clusters, commonly called HElium NanoDroplet Isolation (HENDI) spectroscopy, is an established, powerful experimental technique for extracting high resolution ro-vibrational spectra at ultra-low temperatures. Realistic quantum simulations of such systems, in particular in cases where the solute is undergoing a chemical reaction, require accurate solute-helium potentials which are also simple enough to be efficiently evaluated over the vast number of steps required in typical Monte Carlo or molecular dynamics sampling. This precludes using global potential energy surfaces as often parameterized for small complexes in the realm of high-resolution spectroscopic investigations that, in view of the computational effort imposed, are focused on the intermolecular interaction of rigid molecules with helium. Simple Lennard-Jones-like pair potentials, on the other hand, fall short in providing the required flexibility and accuracy in order to account for chemical reactions of the solute molecule. Here, a general scheme of constructing sufficiently accurate site-site potentials for use in typical quantum simulations is presented. This scheme employs atom-based grids, accounts for local and global minima, and is applied to the special case of a HCl(H(2)O)(4) cluster solvated by helium. As a first step, accurate interaction energies of a helium atom with a set of representative configurations sampled from a trajectory following the dissociation of the HCl(H(2)O)(4) cluster were computed using an efficient combination of density functional theory and symmetry-adapted perturbation theory, i.e. the DFT-SAPT approach. For each of the sampled cluster configurations, a helium atom was placed at several hundred positions distributed in space, leading to an overall number of about 400,000 such quantum chemical calculations. The resulting total interaction energies, decomposed into several energetic contributions, served to fit a site-site potential, where the sites are located at the atomic positions and, additionally, pseudo-sites are distributed along the lines joining pairs of atom sites within the molecular cluster. This approach ensures that this solute-helium potential is able to describe both undissociated molecular and dissociated (zwitter-) ionic configurations, as well as the interconnecting reaction pathway without re-adjusting partial charges or other parameters depending on the particular configuration. Test calculations of the larger HCl(H(2)O)(5) cluster interacting with helium demonstrate the transferability of the derived site-site potential. This specific potential can be readily used in quantum simulations of such HCl/water clusters in bulk helium or helium nanodroplets, whereas the underlying construction procedure can be generalized to other molecular solutes in other atomic solvents such as those encountered in rare gas matrix isolation spectroscopy.


Healthcare resource utilization in myeloproliferative neoplasms: a population-based study from Ontario, Canada.
Health resource utilization (HRU) and associated factors of high cost are not well understood in myeloproliferative neoplasms (MPNs). In this population-based, retrospective matched-cohort study, we used administrative health databases of Ontario, Canada to measure treatment costs and HRU for patients with MPN from 2004 to 2016 and compared them to matched controls. In 7130 patients with MPN [essential thrombocythemia (ET) = 3481; polycythemia vera (PV) = 2618; myelofibrosis (MF) = 1031], the mean annualized treatment costs were $16,646 for ET (controls, $7070); $16,360 for PV (controls, $7293); and $25,863 for MF (controls, $7386). Out of the total costs, the largest expenditure was on acute hospital care (ET: 57%, PV: 57%, MF: 66%). Older age (≥65), male gender, patients not seen by a specialist, and greater comorbidity burden were independent predictors of higher costs (p < 0.05). In addition, history of venous thrombosis in patients with ET and PV was associated with significantly higher treatment costs (p < 0.05).


In vitro method for measuring synthesis rates in the intervertebral disc.
A method for culturing intervertebral disc tissue in vitro under conditions that control changes in hydration and minimize loss of proteoglycans has been developed. Disc slices were enclosed in small-pore dialysis tubing and incubated in medium containing polyethylene glycol (PEG). By varying the PEG concentration, different external swelling pressures could be applied to the tissue. The rate of glycosaminoglycan synthesis in rabbit and dog disc was then measured using [35S]sulphate as a precursor. Synthesis rates varied with final hydration of the tissue, and the highest rates were found at hydrations close to those found in vivo. Under conditions of controlled hydration, rabbit nucleus has a higher rate of glycosaminoglycan synthesis than annulus. However, the rates measured in sagittal slices of dog disc decreased from the outer to the inner regions of the anterior annulus, reaching a minimum value in the nucleus and then increasing again in the posterior part of the annulus. The results show that in the intervertebral disc, measured rates depend on culture conditions.


Prevalence of Helicobacter pylori Infection in Patients with Minimal Hepatic Encephalopathy.
Ammonia is a critical factor in the pathogenesis of minimal hepatic encephalopathy (MHE). Most of the ammonia is from bacterial production in the intestinal tract. Non-absorbable antibiotics and non-absorbable disaccharides are therefore the therapy of choice. A few studies have addressed the effect of ammonia produced by H. pylori in the pathogenesis of MHE. In this prospective clinical trial, 84 consecutive patients with liver cirrhosis (LC) underwent laboratory, psychometric und neurophysiological testing to determine serological H. pylori status, MHE and blood ammonia levels. Relevant clinical and demographic characteristics were documented. Out of 84 LC patients (83% male), 29% presented with MHE as assessed by critical flicker frequency analysis (CFF). The prevalence of H. pylori infection in the cohort was 21%; 22% of H. pylori-infected patients presented with MHE according to the criterion of a positive CFF result. If the criterion for MHE was a positive CFF and a positive NCT-A result, then 17% of H. pylori positive patients suffered from MHE. The prevalence of MHE in H. pylori-negative patients, based on CFF alone and on the combination, was 30%. A proportion of 19% of the patients with MHE had increased blood ammonia levels. The amount of ammonia produced by H. pylori does not affect venous ammonia levels. Therefore, an additional benefit of H. pylori eradication in the treatment of hepatic encephalopathy in patients with LC is unlikely to occur.


Relationship of mammary blood flow to parturition in the ewe.
Mammary blood flow was measured in conscious, unanesthetized ewes with electromagnetic flow probes prior to spontaneous labor (four animals) or during the induction of premature labor (four animals) by administration of dexamethasone, 1 mg/24 h, to the fetus. In all animals an increase in mammary blood flow was noted prior to delivery. Dexamethasone administered to one mother in the same dose did not induce labor or produce an increase in mammary blood flow. These results suggest that the fetal adrenal gland influences maternal mammary blood flow prior to delivery.


Omega 3 fatty acids on child growth, visual acuity and neurodevelopment.
The aim of this review is to evaluate the effects of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) supplementation in pregnant and lactating women and infants during postnatal life, on the visual acuity, psychomotor development, mental performance and growth of infants and children. Eighteen publications (11 sets of randomized control clinical trial [RCTs]) assessed the effects of the n-3 LCPUFA supplementation during pregnancy on neurodevelopment and growth, in the same subjects at different time points; 4 publications (2 data sets from RCTs) addressed physiological responses to n-3 LCPUFA supplementation during pregnancy & lactation and 5 publications (3 data sets from RCTs) exclusively during lactation. Some of these studies showed beneficial effects of docosahexaenoic acid (DHA) supplementation during pregnancy and/or lactation especially on visual acuity outcomes and some on long-term neurodevelopment; a few, showed positive effects on growth. There were also 15 RCTs involving term infants who received infant formula supplemented with DHA, which met our selection criteria. Many of these studies claimed a beneficial effect of such supplementation on visual, neural, or developmental outcomes and no effects on growth. Although new well designed and conducted studies are being published, evidence from RCTs does not demonstrate still a clear and consistent benefit of n-3 LCPUFA supplementation during pregnancy and/or lactation on term infants growth, neurodevelopment and visual acuity. These results should be interpreted with caution due to methodological limitations of the included studies.


An attenuated replication-competent chikungunya virus with a fluorescently tagged envelope.
Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide, causing acute and chronically debilitating arthralgia at a great economic expense. To facilitate our study of CHIKV, we generated a mCherry tagged replication-competent chimeric virus, CHIKV 37997-mCherry. Single particle cryoEM demonstrated icosahedral organization of the chimeric virus and the display of mCherry proteins on virus surface. CHIKV 37997-mCherry is attenuated in both IFNαR knockout and wild-type mice. Strong anti-CHIKV and anti-mCherry antibody responses were induced in CHIKV 37997-mCherry infected mice. Our work suggests that chimeric alphaviruses displaying foreign antigen can serve as vaccines against both aphaviruses and other pathogens and diseases.


A Gauss-Seidel iteration scheme for reference-free 3-D histological image reconstruction.
Three-dimensional (3-D) reconstruction of histological slice sequences offers great benefits in the investigation of different morphologies. It features very high-resolution which is still unmatched by in vivo 3-D imaging modalities, and tissue staining further enhances visibility and contrast. One important step during reconstruction is the reversal of slice deformations introduced during histological slice preparation, a process also called image unwarping. Most methods use an external reference, or rely on conservative stopping criteria during the unwarping optimization to prevent straightening of naturally curved morphology. Our approach shows that the problem of unwarping is based on the superposition of low-frequency anatomy and high-frequency errors. We present an iterative scheme that transfers the ideas of the Gauss-Seidel method to image stacks to separate the anatomy from the deformation. In particular, the scheme is universally applicable without restriction to a specific unwarping method, and uses no external reference. The deformation artifacts are effectively reduced in the resulting histology volumes, while the natural curvature of the anatomy is preserved. The validity of our method is shown on synthetic data, simulated histology data using a CT data set and real histology data. In the case of the simulated histology where the ground truth was known, the mean Target Registration Error (TRE) between the unwarped and original volume could be reduced to less than 1 pixel on average after six iterations of our proposed method.


High-resolution methods for fluorescence retrieval from space.
The retrieval from space of a very weak fluorescence signal was studied in the O(2)A and O(2)B oxygen atmospheric absorption bands. The accuracy of the method was tested for the retrieval of the chlorophyll fluorescence and reflectance terms contributing to the sensor signal. The radiance at the top of the atmosphere was simulated by means of a commercial radiative-transfer program at a high resolution (0.1 cm(-1)). A test data set was generated in order to simulate sun-induced chlorophyll fluorescence at the top of the canopy. Reflectance terms were spectrally modeled using cubic splines and fluorescence by means of the sum of two Voigt functions. Sensor radiance residual minimization was performed in the presence of a multiplicative noise, thus ensuring that the sensor simulations were realistic. The study, which focused on the possibility of retrieving fluorescence with an accuracy better than 10%, was performed for instrument resolutions ranging from about 0.4 cm(-1) to 2 cm(-1) in order to test the algorithm for the characteristics of existing and planned hyper-spectral sensors. The algorithm was also used to retrieve fluorescence in the single O(2)A band at the OCO and TANSO-FTS instrument spectral resolutions.


The Effect of Hearing Aid Use on Cognition in Older Adults: Can We Delay Decline or Even Improve Cognitive Function?
Hearing loss is a modifiable risk factor for dementia in older adults. Whether hearing aid use can delay the onset of cognitive decline is unknown. Participants in this study (aged 62-82 years) were assessed before and 18 months after hearing aid fitting on hearing, cognitive function, speech perception, quality of life, physical activity, loneliness, isolation, mood, and medical health. At baseline, multiple linear regression showed hearing loss and age predicted significantly poorer executive function performance, while tertiary education predicted significantly higher executive function and visual learning performance. At 18 months after hearing aid fitting, speech perception in quiet, self-reported listening disability and quality of life had significantly improved. Group mean scores across the cognitive test battery showed no significant decline, and executive function significantly improved. Reliable Change Index scores also showed either clinically significant improvement or stability in executive function for 97.3% of participants, and for females for working memory, visual attention and visual learning. Relative stability and clinically and statistically significant improvement in cognition were seen in this participant group after 18 months of hearing aid use, suggesting that treatment of hearing loss with hearing aids may delay cognitive decline. Given the small sample size, further follow up is required.


Disentangling the genetic origins of a plant pathogen during disease spread using an original molecular epidemiology approach.
The advent of molecular epidemiology has greatly improved our ability to identify the population sources and track the pathogen movement. Yet the wide spatial and temporal scales usually considered are useful only to infer historical migration pathways. In this study, Bayesian genetic assignments and a landscape epidemiology approach were combined to unravel genetic origin and annual spread during a single epidemic of a plant pathogen: the poplar rust fungus Melampsora larici-populina. The study focused on a particular area-the Durance River valley-which enabled inoculum sources to be identified and channelled spread of the epidemic along a one-dimensional corridor. Spatio-temporal monitoring of disease showed that the epidemic began in the upstream part of the valley and spread out downstream. Using genetic assignment tests, individuals collected at the end of the epidemic were sorted into two genetic groups; very few hybrids were detected, although individuals from both groups coexisted locally downstream in the valley. The epidemic originated from two genetically distinct inoculum sources. Individuals of each group then dispersed southwards along the Durance River and became mixed in poplar riparian stands. These two genetic groups were found previously at a wider spatial scale and proved to result from distinct evolutionary histories on either wild or cultivated poplars. This study showed that the two groups can mix during an epidemic but do not hybridize because they then reproduce asexually. In general, the methods employed here could be useful for elucidating the genetic origin and retracing the colonization history and migration pathways of recent epidemics.


Maternal folate deficiency and metabolic dysfunction in offspring.
The importance of folate during pregnancy was established more than 80 years ago by Lucy Wills' ground-breaking studies of tropical macrocytic anaemia. More recently, it has become apparent that the adverse consequences of inadequate nutrient supply during early developmental may be exacerbated by over-nutrition postnatally. The present paper aims to review recent evidence that maternal methyl donor (notably folate) supply peri-conceptually and during pregnancy has long-term effects on offspring (metabolic) health. In addition, we propose the hypothesis that epigenetic mechanisms, especially DNA methylation, may mediate the effects of these early life nutritional insults. We discuss evidence from a natural experiment in human subjects which provides proof of principle for the hypothesis. We describe an attempt to test this hypothesis using a mouse model in which female C57Bl/6 mice were randomised to low or normal folate diets prior to, and during, pregnancy and lactation. Low maternal folate supply resulted in offspring that were more susceptible to detrimental metabolic effects of a high-fat diet fed from weaning, manifested as increased circulating TAG concentration. Interestingly, this metabolic phenotype in adult offspring occurred without any detectable change in adiposity, suggesting a different aetiological origin from the more commonly reported observation that maternal undernutrition leads to increased offspring adiposity and to symptoms of the Metabolic Syndrome. The widespread prevalence of overweight and obesity and of folate deficiency among women of child-bearing age highlights the possibility that this double nutritional insult may exacerbate the risk of metabolic disease in their offspring.


Structural insight into geranylgeranyl diphosphate synthase (GGDPS) for cancer therapy.
Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anti-cancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential. Here we provide a comprehensive structure-focused review of GGDPS. We reviewed available yeast and human GGDPS structures and then used AlphaFold modeling to complete unsolved structural aspects of these models. We delineate the elements of higher-order structure formation, product-substrate binding, the electrostatic surface, and small molecule inhibitor binding. With the rise of structure-based drug design, the information provided here will serve as a valuable tool for rationally optimizing inhibitor selectivity and effectiveness.


Sorghum Growth Promotion by Paraburkholderia tropica and Herbaspirillum frisingense: Putative Mechanisms Revealed by Genomics and Metagenomics.
Bacteria from the genera Paraburkholderia and Herbaspirillum can promote the growth of Sorghum bicolor, but the underlying mechanisms are not yet known. In a pot experiment, sorghum plants grown on sterilized substrate were inoculated with Paraburkholderia tropica strain IAC/BECa 135 and Herbaspirillum frisingense strain IAC/BECa 152 under phosphate-deficient conditions. These strains significantly increased Sorghum bicolor cultivar SRN-39 root and shoot biomass. Shotgun metagenomic analysis of the rhizosphere revealed successful colonization by both strains; however, the incidence of colonization was higher in plants inoculated with P. tropica strain IAC/BECa 135 than in those inoculated with H. frisingense strain IAC/BECa 152. Conversely, plants inoculated with H. frisingense strain IAC/BECa 152 showed the highest increase in biomass. Genomic analysis of the two inoculants implied a high degree of rhizosphere fitness of P. tropica strain IAC/BECa 135 through environmental signal processing, biofilm formation, and nutrient acquisition. Both genomes contained genes related to plant growth-promoting bacterial (PGPB) traits, including genes related to indole-3-acetate (IAA) synthesis, nitrogen fixation, nodulation, siderophore production, and phosphate solubilization, although the P. tropica strain IAC/BECa 135 genome contained a slightly more extensive repertoire. This study provides evidence that complementary mechanisms of growth promotion in Sorghum might occur, i.e., that P. tropica strain IAC/BECa 135 acts in the rhizosphere and increases the availability of nutrients, while H. frisingense strain IAC/BECa 152 influences plant hormone signaling. While the functional and taxonomic profiles of the rhizobiomes were similar in all treatments, significant differences in plant biomass were observed, indicating that the rhizobiome and the endophytic microbial community may play equally important roles in the complicated plant-microbial interplay underlying increased host plant growth.


Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.
A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.


Characterization of Cu-exchanged SSZ-13: a comparative FTIR, UV-Vis, and EPR study with Cu-ZSM-5 and Cu-β with similar Si/Al and Cu/Al ratios.
Cu-SSZ-13 has been characterized by different spectroscopic techniques and compared with Cu-ZSM-5 and Cu-β with similar Si/Al and Cu/Al ratios and prepared by the same ion exchange procedure. On vacuum activated samples, low temperature FTIR spectroscopy allowed us to appreciate a high concentration of reduced copper centres, i.e. isolated Cu(+) ions located in different environments, able to form Cu(+)(N2), Cu(+)(CO)n (n = 1, 2, 3), and Cu(+)(NO)n (n = 1, 2) upon interaction with N2, CO and NO probe molecules, respectively. Low temperature FTIR, DRUV-Vis and EPR analysis on O2 activated samples revealed the presence of different Cu(2+) species. New data and discussion are devoted to (i) [Cu-OH](+) species likely balanced by one framework Al atom; (ii) mono(μ-oxo)dicopper [Cu2(μ-O)](2+) dimers observed in Cu-ZSM-5 and Cu-β, but not in Cu-SSZ-13. UV-Vis-NIR spectra of O2 activated samples reveal an intense and finely structured d-d quadruplet, unique to Cu-SSZ-13, which is persistent under SCR conditions. This differs from the 22,700 cm(-1) band of the mono(μ-oxo)dicopper species of the O2 activated Cu-ZSM-5, which disappears under SCR conditions. The EPR signal intensity sets Cu-β apart from the others.


Rapid metagenomics analysis of EMS vehicles for monitoring pathogen load using nanopore DNA sequencing.
Pathogen monitoring, detection and removal are essential to public health and outbreak management. Systems are in place for monitoring the microbial load of hospitals and public health facilities with strategies to mitigate pathogen spread. However, no such strategies are in place for ambulances, which are tasked with transporting at-risk individuals in immunocompromised states. As standard culturing techniques require a laboratory setting, and are time consuming and labour intensive, our approach was designed to be portable, inexpensive and easy to use based on the MinION third-generation sequencing platform from Oxford Nanopore Technologies. We developed a transferable sampling-to-analysis pipeline to characterize the microbial community in emergency medical service vehicles. Our approach identified over sixty-eight organisms in ambulances to the genera level, with a proportion of these being connected with health-care associated infections, such as Clostridium spp. and Staphylococcus spp. We also monitored the microbiome of different locations across three ambulances over time, and examined the dynamic community of microorganisms found in emergency medical service vehicles. Observed differences identified hot spots, which may require heightened monitoring and extensive cleaning. Through metagenomics analysis it is also possible to identify how microorganisms spread between patients and colonize an ambulance over time. The sequencing results aid in the development of practices to mitigate disease spread, while also providing a useful tool for outbreak prediction through ongoing analysis of the ambulance microbiome to identify new and emerging pathogens. Overall, this pipeline allows for the tracking and monitoring of pathogenic microorganisms of epidemiological interest, including those related to health-care associated infections.


Histology, imaging and new diagnostic work-flows in pathology.
Since their introduction in 1999, fully automated, high speed, high-resolution whole slide imaging devices have become increasing more reliable, fast and capable. While by no means perfect, these devices have evolved to a point where one can consider placing them in a pre-diagnostic role in a clinical histology lab. At the Massachusetts General Hospital, we are running a pilot study placing high end WSI devices in our main clinical histology lab (after the cover slipper and before slides are sent to the pathologist) to examine the requirement for both the machine and the laboratory. Placing WSI systems in the clinical lab stresses the system in terms of reliability and throughput. Significantly however, success requires significant modification to the lab workflow. It is likely laboratories need to move from manual, large batch processes to increasingly automated, continuous flow (or mini-batch) processes orchestrated by the LIS using bar coding to track and direct slides, and incorporating the decision to image into the specimen type and the histology orders. Furthermore, image quality, capture speed and reliability are functions of the quality of the histology presented to the WSI devices. Imaging in pathology does not begin in a WSI robot but in the grossing room and in the histology lab. As more and more imaging devices are placed in histology lab, the inter-relationships histology and pathology imaging will become increasing understood.


Children With Dyslexia Benefit From Orthographic Facilitation During Spoken Word Learning.
Orthographic facilitation describes the phenomenon in which a spoken word is produced more accurately when its corresponding written word is present during learning. We examined the orthographic facilitation effect in children with dyslexia because they have poor learning and recall of spoken words. We hypothesized that including orthography during spoken word learning would facilitate learning and recall. Children with dyslexia and children with typical development (n = 46 per group), 7-9 years old, were matched for grade and nonverbal intelligence. Across 4 blocks of exposure in 1 session, children learned pairings between 4 spoken pseudowords and novel semantic referents in a modified paired-associate learning task. Two of the pairings were presented with orthography present, and 2 were presented with orthography absent. Recall of newly learned spoken words was assessed using a naming task. Both groups showed orthographic facilitation during learning and naming. During learning, both groups paired pseudowords and referents more accurately when orthography was present. During naming, children with typical development showed a large orthographic facilitation effect that increased across blocks. For children with dyslexia, this effect was present initially but then plateaued. We demonstrate for the first time that children with dyslexia benefit from orthographic facilitation during spoken word learning. These findings have direct implications for teaching spoken vocabulary to children with dyslexia.


Human presence impacts fungal diversity of inflated lunar/Mars analog habitat.
An inflatable lunar/Mars analog habitat (ILMAH), simulated closed system isolated by HEPA filtration, mimics International Space Station (ISS) conditions and future human habitation on other planets except for the exchange of air between outdoor and indoor environments. The ILMAH was primarily commissioned to measure physiological, psychological, and immunological characteristics of human inhabiting in isolation, but it was also available for other studies such as examining its microbiological aspects. Characterizing and understanding possible changes and succession of fungal species is of high importance since fungi are not only hazardous to inhabitants but also deteriorate the habitats. Observing the mycobiome changes in the presence of human will enable developing appropriate countermeasures with reference to crew health in a future closed habitat. Succession of fungi was characterized utilizing both traditional and state-of-the-art molecular techniques during the 30-day human occupation of the ILMAH. Surface samples were collected at various time points and locations to observe both the total and viable fungal populations of common environmental and opportunistic pathogenic species. To estimate the cultivable fungal population, potato dextrose agar plate counts method was utilized. The internal transcribed spacer region-based iTag Illumina sequencing was employed to measure the community structure and fluctuation of the mycobiome over time in various locations. Treatment of samples with propidium monoazide (PMA; a DNA intercalating dye for selective detection of viable microbial populations) had a significant effect on the microbial diversity compared to non-PMA-treated samples. Statistical analysis confirmed that viable fungal community structure changed (increase in diversity and decrease in fungal burden) over the occupation time. Samples collected at day 20 showed distinct fungal profiles from samples collected at any other time point (before or after). Viable fungal families like Davidiellaceae, Teratosphaeriaceae, Pleosporales, and Pleosporaceae were shown to increase during the occupation time. The results of this study revealed that the overall fungal diversity in the closed habitat changed during human presence; therefore, it is crucial to properly maintain a closed habitat to preserve it from deteriorating and keep it safe for its inhabitants. Differences in community profiles were observed when statistically treated, especially of the mycobiome of samples collected at day 20. On a genus level Epiccocum, Alternaria, Pleosporales, Davidiella, and Cryptococcus showed increased abundance over the occupation time.


Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures.
Stem cell-based therapy of retinal degenerative conditions is a promising modality to treat blindness, but requires new strategies to improve the number of functionally integrating cells. Grafting semidifferentiated retinal tissue rather than progenitors allows preservation of tissue structure and connectivity in retinal grafts, mandatory for vision restoration. Using human embryonic stem cells (hESCs), we derived retinal tissue growing in adherent conditions consisting of conjoined neural retina and retinal pigment epithelial (RPE) cells and evaluated cell fate determination and maturation in this tissue. We found that deriving such tissue in adherent conditions robustly induces all eye field genes (RX, PAX6, LHX2, SIX3, SIX6) and produces four layers of pure populations of retinal cells: RPE (expressing NHERF1, EZRIN, RPE65, DCT, TYR, TYRP, MITF, PMEL), early photoreceptors (PRs) (coexpressing CRX and RCVRN), inner nuclear layer neurons (expressing CALB2), and retinal ganglion cells [RGCs, expressing BRN3B and Neurofilament (NF) 200]. Furthermore, we found that retinal progenitors divide at the apical side of the hESC-derived retinal tissue (next to the RPE layer) and then migrate toward the basal side, similar to that found during embryonic retinogenesis. We detected synaptogenesis in hESC-derived retinal tissue, and found neurons containing many synaptophysin-positive boutons within the RGC and PR layers. We also observed long NF200-positive axons projected by RGCs toward the apical side. Whole-cell recordings demonstrated that putative amacrine and/or ganglion cells exhibited electrophysiological responses reminiscent of those in normal retinal neurons. These responses included voltage-gated Na(+) and K(+) currents, depolarization-induced spiking, and responses to neurotransmitter receptor agonists. Differentiation in adherent conditions allows generation of long and flexible pieces of 3D retinal tissue suitable for isolating transplantable slices of tissue for retinal replacement therapies.


Genomic analysis reveals major determinants of cis-regulatory variation in Capsella grandiflora.
Understanding the causes of cis-regulatory variation is a long-standing aim in evolutionary biology. Although cis-regulatory variation has long been considered important for adaptation, we still have a limited understanding of the selective importance and genomic determinants of standing cis-regulatory variation. To address these questions, we studied the prevalence, genomic determinants, and selective forces shaping cis-regulatory variation in the outcrossing plant Capsella grandiflora We first identified a set of 1,010 genes with common cis-regulatory variation using analyses of allele-specific expression (ASE). Population genomic analyses of whole-genome sequences from 32 individuals showed that genes with common cis-regulatory variation (i) are under weaker purifying selection and (ii) undergo less frequent positive selection than other genes. We further identified genomic determinants of cis-regulatory variation. Gene body methylation (gbM) was a major factor constraining cis-regulatory variation, whereas presence of nearby transposable elements (TEs) and tissue specificity of expression increased the odds of ASE. Our results suggest that most common cis-regulatory variation in C. grandiflora is under weak purifying selection, and that gene-specific functional constraints are more important for the maintenance of cis-regulatory variation than genome-scale variation in the intensity of selection. Our results agree with previous findings that suggest TE silencing affects nearby gene expression, and provide evidence for a link between gbM and cis-regulatory constraint, possibly reflecting greater dosage sensitivity of body-methylated genes. Given the extensive conservation of gbM in flowering plants, this suggests that gbM could be an important predictor of cis-regulatory variation in a wide range of plant species.


Rapid influx and death of plasmacytoid dendritic cells in lymph nodes mediate depletion in acute simian immunodeficiency virus infection.
Plasmacytoid dendritic cells (pDC) are essential innate immune system cells that are lost from the circulation in human immunodeficiency virus (HIV)-infected individuals associated with CD4(+) T cell decline and disease progression. pDC depletion is thought to be caused by migration to tissues or cell death, although few studies have addressed this directly. We used precise methods of enumeration and in vivo labeling with 5-bromo-2'-deoxyuridine to track recently divided pDC in blood and tissue compartments of monkeys with acute pathogenic simian immunodeficiency virus (SIV) infection. We show that pDC are lost from blood and peripheral lymph nodes within 14 days of infection, despite a normal frequency of pDC in bone marrow. Paradoxically, pDC loss masked a highly dynamic response characterized by rapid pDC mobilization into blood and a 10- to 20-fold increase in recruitment to lymph nodes relative to uninfected animals. Within lymph nodes, pDC had increased levels of apoptosis and necrosis, were uniformly activated, and were infected at frequencies similar to CD4(+) T cells. Nevertheless, remaining pDC had essentially normal functional responses to stimulation through Toll-like receptor 7, with half of lymph node pDC producing both TNF-alpha and IFN-alpha. These findings reveal that cell migration and death both contribute to pDC depletion in acute SIV infection. We propose that the rapid recruitment of pDC to inflamed lymph nodes in lentivirus infection has a pathologic consequence, bringing cells into close contact with virus, virus-infected cells, and pro-apoptotic factors leading to pDC death.


Evidence-based mental health use of anticonvulsants during pregnancy.
There are many pertinent issues surrounding the treatment of bipolar disorder during pregnancy. Unfortunately, while there are numerous observational reports in the literature, there is not a lot of information concerning the safety and efficacy of particular treatments or the nontreatment of bipolar disorder during pregnancy. Much of the existing data comes from the neurology literature regarding epilepsy. In this review, we summarize the available evidence regarding the safety and efficacy of using the anticonvulsants carbamazepine and valproic acid during pregnancy. The available data suggest that there is a possibility of risk of major malformations with the anticonvulsants. The risk is probably higher with valproic acid than carbamazepine. In this article lithium is not discussed, although there are a number of concerns about lithium's potential teratogenicity, and it has been implicated in Epstein's anomaly, a congenital heart defect among infants born to women taking lithium; as with other medications, however, the data have specific limitations.


Perturbation-response scanning reveals ligand entry-exit mechanisms of ferric binding protein.
We study apo and holo forms of the bacterial ferric binding protein (FBP) which exhibits the so-called ferric transport dilemma: it uptakes iron from the host with remarkable affinity, yet releases it with ease in the cytoplasm for subsequent use. The observations fit the "conformational selection" model whereby the existence of a weakly populated, higher energy conformation that is stabilized in the presence of the ligand is proposed. We introduce a new tool that we term perturbation-response scanning (PRS) for the analysis of remote control strategies utilized. The approach relies on the systematic use of computational perturbation/response techniques based on linear response theory, by sequentially applying directed forces on single-residues along the chain and recording the resulting relative changes in the residue coordinates. We further obtain closed-form expressions for the magnitude and the directionality of the response. Using PRS, we study the ligand release mechanisms of FBP and support the findings by molecular dynamics simulations. We find that the residue-by-residue displacements between the apo and the holo forms, as determined from the X-ray structures, are faithfully reproduced by perturbations applied on the majority of the residues of the apo form. However, once the stabilizing ligand (Fe) is integrated to the system in holo FBP, perturbing only a few select residues successfully reproduces the experimental displacements. Thus, iron uptake by FBP is a favored process in the fluctuating environment of the protein, whereas iron release is controlled by mechanisms including chelation and allostery. The directional analysis that we implement in the PRS methodology implicates the latter mechanism by leading to a few distant, charged, and exposed loop residues. Upon perturbing these, irrespective of the direction of the operating forces, we find that the cap residues involved in iron release are made to operate coherently, facilitating release of the ion.


Calmodulin involvement in stress-activated nuclear localization of albumin in JB6 epithelial cells.
We report that albumin is translocated to the nucleus in response to oxidative stress. Prior measurements have demonstrated that in concert with known transcription factors albumin binds to an antioxidant response element, which controls the expression of glutathione S-transferase and other antioxidant enzymes that function to mediate adaptive cellular responses [Holderman, M. T., Miller, K. P., Dangott, L. J., and Ramos, K. S. (2002) Mol. Pharmacol. 61, 1174-1183]. To investigate the mechanisms underlying this adaptive cell response, we have identified linkages between calcium signaling and the nuclear translocation of albumin in JB6 epithelial cells. Under resting conditions, albumin and the calcium regulatory protein calmodulin (CaM) co-immunoprecipitate using antibodies against either protein, indicating a tight association. Calcium activation of CaM disrupts the association between CaM and albumin, suggesting that transient increases in cytosolic calcium levels function to mobilize intracellular albumin to facilitate its translocation into the nucleus. Likewise, nuclear translocation of albumin is induced by exposure of cells to hydrogen peroxide or a phorbol ester, indicating a functional linkage between reactive oxygen species, calcium, and PKC-signaling pathways. Inclusion of an antioxidant enzyme (i.e., superoxide dismutase) blocks nuclear translocation, suggesting that the oxidation of sensitive proteins functions to coordinate the adaptive cellular response. These results suggest that elevated calcium transients and associated increases in reactive oxygen species contribute to adaptive cellular responses through the mobilization and nuclear translocation of cellular albumin.


Multipolar migration: the third mode of radial neuronal migration in the developing cerebral cortex.
Two distinct modes of radial neuronal migration, locomotion and somal translocation, have been reported in the developing cerebral cortex. Although these two modes of migration have been well documented, the cortical intermediate zone contains abundant multipolar cells, and they do not resemble the cells migrating by locomotion or somal translocation. Here, we report that these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. Time-lapse analysis of living slices revealed that the multipolar cells do not have any fixed cell polarity, and that they very dynamically extend and retract multiple processes as their cell bodies slowly move. They do not usually move straight toward the pial surface during their radial migration, but instead frequently change migration direction and rate; sometimes they even remain in almost the same position, especially when they are in the subventricular zone. Occasionally, the multipolar cells jump tangentially during their radial migration. Because the migration modality of these cells clearly differs from locomotion or somal translocation, we refer to their novel type of migration as "multipolar migration." In view of the high proportion of cells exhibiting multipolar migration, this third mode of radial migration must be an important type of migration in the developing cortex.


Sodium selenide toxicity is mediated by O2-dependent DNA breaks.
Hydrogen selenide is a recurrent metabolite of selenium compounds. However, few experiments studied the direct link between this toxic agent and cell death. To address this question, we first screened a systematic collection of Saccharomyces cerevisiae haploid knockout strains for sensitivity to sodium selenide, a donor for hydrogen selenide (H(2)Se/HSe(-/)Se(2-)). Among the genes whose deletion caused hypersensitivity, homologous recombination and DNA damage checkpoint genes were over-represented, suggesting that DNA double-strand breaks are a dominant cause of hydrogen selenide toxicity. Consistent with this hypothesis, treatment of S. cerevisiae cells with sodium selenide triggered G2/M checkpoint activation and induced in vivo chromosome fragmentation. In vitro, sodium selenide directly induced DNA phosphodiester-bond breaks via an O(2)-dependent reaction. The reaction was inhibited by mannitol, a hydroxyl radical quencher, but not by superoxide dismutase or catalase, strongly suggesting the involvement of hydroxyl radicals and ruling out participations of superoxide anions or hydrogen peroxide. The (•)OH signature could indeed be detected by electron spin resonance upon exposure of a solution of sodium selenide to O(2). Finally we showed that, in vivo, toxicity strictly depended on the presence of O(2). Therefore, by combining genome-wide and biochemical approaches, we demonstrated that, in yeast cells, hydrogen selenide induces toxic DNA breaks through an O(2)-dependent radical-based mechanism.


Microsatellite markers used for genome-wide association mapping of partial resistance to Sclerotinia sclerotiorum in a world collection of Brassica napus.
The fungal pathogen Sclerotinia sclerotiorum causes stem rot of oilseed rape (Brassica napus) worldwide. In preparation for genome-wide association mapping (GWAM) of sclerotinia resistance in B. napus, 152 accessions from diverse geographical regions were screened with a single Canadian isolate, #321. Plants were inoculated by attaching mycelium plugs to the main stem at full flower. Lesion lengths measured 7, 14 and 21 days after inoculation were used to calculate the area under the disease progress curve (AUDPC). Depth of penetration was noted and used to calculate percent soft and collapsed lesions (% s + c). The two disease traits were highly correlated (r = 0.93). Partially resistant accessions (AUDPC <7 and % s + c <2) were identified primarily from South Korea and Japan with a few from Pakistan, China and Europe. Genotyping of accessions with 84 simple sequence repeat markers provided 690 polymorphic loci for GWAM. The general linear model in TASSEL best fitted the data when adjusted for population structure (STRUCTURE), GLM + Q. After correction for positive false discovery rate, 34 loci were significantly associated with both disease traits of which 21 alleles contributed to resistance, while the remaining enhanced susceptibility. The phenotypic variation explained by the loci ranged from 6 to 25 %. Five loci mapped to published quantitative trait loci conferring sclerotinia resistance in Chinese lines.


FISH as an effective diagnostic tool for the management of challenging melanocytic lesions.
The accuracy of melanoma diagnosis continues to challenge the pathology community, even today with sophisticated histopathologic techniques. Melanocytic lesions exhibit significant morphological heterogeneity. While the majority of biopsies can be classified as benign (nevus) or malignant (melanoma) using well-established histopathologic criteria, there exists a cohort for which the prediction of clinical behaviour and invasive or metastatic potential is difficult if not impossible to ascertain on the basis of morphological features alone. Multiple studies have shown that there is significant disagreement between pathologists and even expert dermatopathologists in the diagnosis of this subgroup of difficult melanocytic lesions. A four probe FISH assay was utilized to analyse a cohort of 500 samples including 157 nevus, 176 dysplastic nevus and 167 melanoma specimens. Review of the lesions determined the assay identified genetic abnormalities in a total of 83.8% of melanomas, and 1.9% of nevus without atypia, while genetic abnormalities were identified in 6.3%, 6.7%, and 10.3% of nevus identified with mild, moderate and severe atypia, respectively. Based on this study, inheritable genetic damage/instability identified by FISH testing is a hallmark of a progressive malignant process, and a valuable diagnostic tool for the identification of high risk lesions.


Probabilistic Measurement of Central Line-Associated Bloodstream Infections.
To develop a probabilistic method for measuring central line-associated bloodstream infection (CLABSI) rates that reduces the variability associated with traditional, manual methods of applying CLABSI surveillance definitions. Multicenter retrospective cohort study of bacteremia episodes among patients hospitalized in adult patient-care units; the study evaluated presence of CLABSI. Hospitals that used SafetySurveillor software system (Premier) and who also reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). Patients were identified from a stratified sample from all eligible blood culture isolates from all eligible hospital units to generate a final set with an equal distribution (ie, 20%) from each unit type. Units were divided a priori into 5 major groups: medical intensive care unit, surgical intensive care unit, medical-surgical intensive care unit, hematology unit, or general medical wards. Episodes were reviewed by 2 experts, and a selection of discordant reviews were re-reviewed. Data were joined with NHSN data for hospitals for in-plan months. A predictive model was created; model performance was assessed using the c statistic in a validation set and comparison with NHSN reported rates for in-plan months. A final model was created with predictors of CLABSI. The c statistic for the final model was 0.75 (0.68-0.80). Rates from regression modeling correlated better with expert review than NHSN-reported rates. The use of a regression model based on the clinical characteristics of the bacteremia outperformed traditional infection preventionist surveillance compared with an expert-derived reference standard. Infect.


Critical evaluation of energy intake data using fundamental principles of energy physiology: 1. Derivation of cut-off limits to identify under-recording.
This paper uses fundamental principles of energy physiology to define minimum cut-off limits for energy intake below which a person of a given sex, age and body weight could not live a normal life-style. These have been derived from whole-body calorimeter and doubly-labelled water measurements in a wide range of healthy adults after due statistical allowance for intra- and interindividual variance. The tabulated cut-off limits, which depend on sample size and duration of measurements, identify minimum plausible levels of energy expenditure expressed as a multiple of basal metabolic rate (BMR). CUT-OFF 1 tests whether reported energy intake measurements can be representative of long-term habitual intake. It is set at 1.35 x BMR for cases where BMR has been measured rather than predicted. CUT-OFF 2 tests whether reported energy intakes are a plausible measure of the food consumed during the actual measurement period, and is always more liberal than CUT-OFF 1 since it has to allow for the known measurement imprecision arising from the high level of day-to-day variability in food intake. The cut-off limits can be used to evaluate energy intake data. Results falling below these limits must be recognized as being incompatible with long-term maintenance of energy balance and therefore with long-term survival.


[A skin lymphoepithelial tumor (skin lymphadenoma)].
The study of a case of cutaneous lymphadenoma and a literature review allowed us to verify that, in contrast to immunohistochemical findings, clinical and histological dates are basically reproducible. Accordingly the eccrine or hair follicle natures of the pleonasm cannot be either excluded or confirmed. The initial terms "cutaneous lympho-epithelial tumor" or "epithelial lymphohistiocytic tumor" seem more suitable than that of "cutaneous lymphadenoma" to describe this peculiar skin neoplasm.


Administration of umbilical cord blood cells transiently decreased hypoxic-ischemic brain injury in neonatal rats.
This study aimed to investigate whether the administration of mononuclear cells derived from human umbilical cord blood cells (UCBCs) could ameliorate hypoxic-ischemic brain injury in a neonatal rat model. The left carotid arteries of 7-day-old rats were ligated, and the rats were then exposed to 8% oxygen for 60 min. Mononuclear cells derived from UCBCs using the Ficoll-Hypaque technique were injected intraperitoneally 6 h after the insult (1.0 × 10(7) cells). Twenty-four hours after the insult, the number of cells positive for the oxidative stress markers 4-hydroxy-2-nonenal and nitrotyrosine, in the dentate gyrus of the hippocampus in the UCBC-treated group, decreased by 36 and 42%, respectively, compared with those in the control group. In addition, the number of cells positive for the apoptosis markers active caspase-3 and apoptosis-inducing factor decreased by 53 and 58%, respectively. The number of activated microglia (ED1-positive cells) was 51% lower in the UCBC group compared with the control group. In a gait analysis performed 2 weeks after the insult, there were no significant differences among the sham-operated, control and UCBC groups. An active avoidance test using a shuttle box the following week also revealed no significant differences among the groups. Neither the volumes of the hippocampi, corpus callosum and cortices nor the numbers of neurons in the hippocampus were different between the UCBC and control groups. In summary, a single intraperitoneal injection of UCBC-derived mononuclear cells 6 h after an ischemic insult was associated with a transient reduction in numbers of apoptosis and oxidative stress marker-positive cells, but it did not induce long-term morphological or functional protection. Repeated administration or a combination treatment may be required to achieve sustained protection.


Computation of canting errors in heliostats by flux map fitting: experimental assessment.
In solar tower plants, thousands of heliostats reflect sunlight into a central receiver. Heliostats consist of a subset of mirrors called facets that must be perfectly oriented (i.e., canted) to concentrate as much solar radiation as possible. This study presents and validates the so-called flux map fitting technique to detect and correct canting errors. The computed distributions were matched to a series of images through an optimization algorithm. According to the sensitivity analysis, three images spread along a single day provide sufficient information for the algorithm to succeed. Using this methodology, four heliostats at the THEMIS research facility were recanted, thereby substantially increasing the optical quality in three of them. The procedure to infer the heliostat aimpoint was assessed.


Enterococci highly resistant to penicillin and ampicillin: an emerging clinical problem?
Sixteen clinical isolates of ampicillin-resistant enterococci (ARE) were recovered from the microbiology laboratory of a 450-bed rehabilitation medical center from January 1981 to September 1987. These isolates were detected when a disk diffusion test using 10 micrograms of ampicillin on a blood agar plate revealed no zones of inhibition. Tube macrodilution tests yielded an MIC of greater than or equal to 16 micrograms of ampicillin per ml. None of the isolates were penicillinase producers by the chromogenic cephalosporin disk test. Ten isolates were Enterococcus faecium, four isolates were E. raffinosus, one isolate was E. gallinarum, and one isolate was not identified (lost). There were 6 male and 10 female patients. The sources of isolates were urine (n = 7), wound (n = 5), ascitic fluid (n = 2), blood (n = 2), peritoneal catheter tip (n = 1), Bartholin's cyst abscess (n = 1), rectal swab (n = 2), and pancreatic abscess (n = 1). The organism was isolated from multiple sites in 4 patients, was a pure culture isolate in 5 patients, and was part of a polymicrobial flora in 11 patients. Six patients were diabetic, and four had liver cirrhosis. All but four patients had received at least one antibiotic within 3 weeks of ARE isolation. The MICs (micrograms per milliliter) for 50 and 90% of isolates tested, respectively, were as follows: ampicillin, 64 and 64; penicillin, 128 and greater than 128; vancomycin, 1 and 2; gentamicin, 4 and 16; ciprofloxacin, 1.6 and 3.2; imipenem, 128 and greater than 128; and daptomycin (LY146032), 1.6 and 6.4. ARE may be an emerging pathogen in the hospitalized patient population.


Effect of a two-stage intervention package on the cesarean section rate in Guangzhou, China: A before-and-after study.
The cesarean section (CS) rate has risen globally during the last two decades. Effective and feasible strategies are needed to reduce it. The aim of this study was to assess the CS rate change after a two-stage intervention package that was designed to reduce the overall CS rate in Guangzhou, China. This intervention package was implemented by the Health Commission of Guangzhou Municipality in 2 stages (October 2010-September 2014 and October 2014-December 2016) and included programs for population health education, skills training for healthcare professionals, equipment and technical support for local healthcare facilities, and capacity building for the maternal near-miss care system. A retrospective repeated cross-sectional study was conducted to evaluate influences of the intervention on CS rates. A pre-intervention period from January 2008 to September 2010 served as the baseline. The primary outcome was the CS rate, and the secondary outcomes included maternal mortality ratio (MMR) and perinatal mortality rate (PMR), all obtained from the Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS). The Cochran-Armitage test was used to examine the trends of the overall CS rate, MMR, and PMR across different stages. Segmented linear regression analysis was used to assess the change of the CS rate over the intervention period. A total of 1,921,932 records of births and 108 monthly CS rates from 2008 to 2016 were analyzed. The monthly CS rate declined across the intervention stages (Z = 75.067, p < 0.001), with an average rate of 42.4% at baseline, 39.8% at Stage 1, and 35.0% at Stage 2. The CS rate declined substantially among nulliparous women who delivered term singletons, with an accelerating decreasing trend observed across Stage 1 and Stage 2 (the difference in slopes: -0.09 [95% CI -0.16 to -0.02] between Stage 1 and baseline, p = 0.014; -0.11 [95% CI -0.20 to -0.02] between Stage 1 and Stage 2, p = 0.017). The CS rate in the remaining population increased during baseline and Stage 1 and subsequently decreased during Stage 2. The sensitivity analysis suggested no immediate impact of the universal two-child policy on the trend of the CS rate. The MMR (Z = -4.368, p < 0.001) and PMR (Z = -13.142, p < 0.001) declined by stage over the intervention period. One of the main limitations of the study is the lack of a parallel control group. Moreover, the influence of temporal changes in the study population on the CS rate was unknown. Given the observational nature of the present study, causality cannot be confirmed. Apparent decline in the overall CS rate was observed in Guangzhou, China, after the implementation of a two-stage intervention package. The decline was most evident among nulliparous women who delivered term singletons. Despite some limitations for causal inference, Guangzhou's experience in controlling the CS rate by implementing composite interventions with public health education and perinatal healthcare service improvement could have implications for other similar areas with high rates of CS.


Protective properties of quercetin against DNA damage and oxidative stress induced by methylmercury in rats.
Aim of the study was to find out whether consumption of quercetin (QC), an abundant flavonoid in the human diet, protects against DNA damage caused by exposure to organic mercury. Therefore, rats were treated orally with methylmercury (MeHg) and the flavonoid with doses that reflect the human exposure. The animals received MeHg (30 μg/kg/bw/day), QC (0.5-50 mg/kg/bw/day), or combinations of both over 45 days. Subsequently, the glutathione levels (GSH) and the activities of glutathione peroxidase (GPx) and catalase (CAT) were determined, and DNA damage was measured in hepatocytes and peripheral leukocytes in single cell gel electrophoresis assays. MeHg decreased the concentration of GSH and the activity of GPx by 17 and 12%, respectively and caused DNA damage to liver and blood cells, while with QC no such effects were seen. When the flavonoid was given in combination with MeHg, the intermediate and the highest concentrations (5.0 and 50.0 mg/kg/bw/day) were found to cause DNA protection; DNA migration was reduced by 54 and 65% in the hepatocytes and by 27 and 36% in the leukocytes; furthermore, the reduction in GSH and GPx levels caused by MeHg treatment was restored. In summary, our results indicate that consumption of QC-rich foods may protect Hg-exposed humans against the adverse health effects of the metal.


Which implant should we use for primary total hip replacement? A systematic review and meta-analysis.
Many total hip implants are currently available on the market worldwide. We aimed to estimate the probability of revision surgery at ten years for each individual total hip implant and to compare these estimates with the National Institute for Health and Care Excellence (NICE) benchmark. We performed a meta-analysis of cohort studies. The methodological quality was assessed with use of the Assessment of Quality in Lower Limb Arthroplasty (AQUILA) checklist. We searched PubMed, Embase, Web of Science, and the Cochrane Library. Additionally, national joint registries that were full members of the International Society of Arthroplasty Registers (ISAR) were hand searched. Studies in which the authors reported the survival probability for either the acetabular or the femoral component of primary total hip replacements with use of revision for any reason or for aseptic loosening at ten years as the end point, with at least 100 implants at baseline, and in which at least 60% of the patients had primary osteoarthritis were eligible for inclusion. The search strategy revealed 5513 papers describing survival probabilities for thirty-four types of acetabular components and thirty-two types of femoral components. Eight types of acetabular cups and fifteen types of femoral stems performed better than the NICE benchmark. We recommend that surgeons performing a primary total hip replacement use an implant that outperforms the NICE benchmarks.


Function in elderly cancer survivors depends on comorbidities.
Factors associated with functional status in elderly cancer survivors, in particular, comorbidity, have been inadequately studied. Of 4162 participants aged 65 and older enrolled in the Duke Established Populations for Epidemiologic Studies of the Elderly study in 1986, 376 of the participants self-reported a diagnosis of cancer. Participants were divided into 2 comorbidity groups and 4 cancer groups. Cancer groups included 132 participants diagnosed 0-4 years ago, 117 diagnosed 5-15 years ago, 127 diagnosed >15 years ago, and 3784 participants who had never been diagnosed with cancer. Comorbidity (self-reported stroke, diabetes, hypertension, and myocardial infarction) was classified as presence of 1 or no comorbidities (n = 3089) or 2 or more comorbidities (n = 1073). Function was assessed by Katz Activities of Daily Living, Rosow-Breslau, Nagi, and Instrumental Activities of Daily Living scales at the time of interview. In a two-way analysis of covariance model of comorbidity and cancer group controlling for age, race, sex, education, marital status, depression, and cognitive status, duration of cancer survivorship does not influence most measures of function. In the subset of 376 cancer survivors, comorbidity significantly correlates with the functional status of these older cancer survivors (<0.02, for all 4 measures of function). In the older cancer survivor, regardless of duration following diagnosis, the presence of comorbidity rather than the history of cancer per se correlates with impaired functional status.


α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.
Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that α-synuclein-containing (α-syn-containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of α-syn from host to graft, followed by seeding of α-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed α-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP- or DsRed-tagged α-syn resulted in a gradual increase in double-labeled cells. Importantly, α-syn-GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-α-syn, suggesting a seeding effect of transmitted α-syn. Extracellular α-syn was taken up by cells through endocytosis and interacted with intracellular α-syn. Next, following intracortical injection of recombinant α-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of α-syn between host cells and grafted dopaminergic neurons in mice overexpressing human α-syn. In summary, intercellularly transferred α-syn interacts with cytoplasmic α-syn and can propagate α-syn pathology. These results suggest that α-syn propagation is a key element in the progression of Parkinson disease pathology.


An Intervention with Mineral Water Decreases Cardiometabolic Risk Biomarkers. A Crossover, Randomised, Controlled Trial with Two Mineral Waters in Moderately Hypercholesterolaemic Adults.
Water intake is essential for health maintenance and disease prevention. The effects of an intervention with two mineral waters, sodium-bicarbonated mineral water (BW) or control mineral water low in mineral content (CW), on cardiometabolic risk biomarkers were studied. In a randomised-controlled crossover-trial, sixty-four moderately hypercholesterolaemic adults were randomly assigned to consume 1 L/day of either BW (sodium, 1 g/L; bicarbonate, 2 g/L) or CW with the main meals for eight weeks, separated by an eight-week washout period. Blood lipids, lipid oxidation, glucose, insulin, aldosterone, urine pH, urinary electrolytes, blood pressure, body weight, fluid intake, energy, and nutrients from total diet and beverages were determined. Total cholesterol, LDL cholesterol, and glucose decreased (p < 0.01), oxidised LDL tended to decrease (p = 0.073), and apolipoprotein B increased during the intervention, without water type effect. Energy and carbohydrates from beverages decreased since soft drinks and fruit juice consumptions decreased throughout the trial. BW increased urinary pH (p = 0.006) and reduced calcium/creatinine excretion (p = 0.011). Urinary potassium/creatinine decreased with both waters. Consumption of 1 L/day of mineral water with the main meals reduces cardiometabolic risk biomarkers, likely to be attributed to a replacement of soft drinks by water. In addition, BW does not affect blood pressure and exerts a moderate alkalizing effect in the body.


The effect of macrolides on myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts.
Macrolides are known to have anti-inflammatory, immunomodulatory, and tissue reparative effects. The purpose of this study was to determine the effect of macrolides (erythromycin [EM] and roxithromycin [RXM]) on the differentiation of fibroblasts into myofibroblasts and extracellular matrix accumulation in transforming growth factor (TGF) beta1-induced nasal polyp-derived fibroblasts (NPDFs) and to determine if NADPH oxidase (Nox) 4 and reactive oxygen species (ROS) are involved in the aforementioned processes. Nasal polyps of six patients (three women and three men; 32.3 ± 5.2 years of age) were acquired during surgery and NPDFs were isolated from surgical tissues. NPDFs were pretreated with macrolides for 2 hours before differentiation induction by TGF-beta1. The mRNA expressions of alpha-smooth muscle actin (SMA), collagen types I and III, and Nox4 were determined by reverse-transcription-polymerase chain reaction, and the expression of alpha-SMA protein was determined by immunocytochemical staining. The amount of total collagen production was analyzed by SirCol collagen dye-binding assay. ROS activity was measured by nitroblue tetrazolium reduction assay and was visualized by fluorescent microscopy. In TGF-beta1-induced NPDFs, EM, and RXM significantly inhibited expressions of alpha-SMA and collagen types I and III mRNA and reduced alpha-SMA and collagen protein levels at concentrations of 5 and 10 μg/mL. EM and RXM also inhibited TGF-β1-induced ROS production and Nox4 mRNA expression at the same concentrations. These results suggest the possibility that EM and RXM may play an important role in inhibiting the development of nasal polyps through their antioxidant effect.


Parental feeding practices and child weight status in Mexican American families: a longitudinal analysis.
Parental feeding practices are thought to influence children's weight status, through children's eating behavior and nutritional intake. However, because most studies have been cross-sectional, the direction of influence is unclear. Moreover, although obesity rates are high among Latino children, few studies of parental feeding practices have focused on this population. This 2-year longitudinal study examined mutual influences over time between parental feeding practices and children's weight status, in Mexican American families with children 18 years old at baseline. Mothers (n = 322) and fathers (n = 182) reported on their feeding practices at baseline, 1-year follow-up, and 2-year follow-up. Weight status, defined by waist-height ratio (WHtR) and body mass index (BMI), was ascertained at all assessments. Cross-lagged panel models were used to examine the mutual influences of parental feeding practices and child weight status over time, controlling for covariates. Both mothers' and fathers' restriction of food predicted higher subsequent child weight status at Year 1, and for fathers this effect was also found at Year 2. Mothers' and fathers' pressure to eat predicted lower weight status among boys, but not girls, at Year 1. Child weight status also predicted some parental feeding practices: boys' heavier weight predicted mothers' less pressure to eat at Year 1, less use of food to control behavior at Year 2, and greater restriction at Year 2; and girls' heavier weight at Year 1 predicted fathers' less pressure to eat and less positive involvement in child eating at Year 2. This study provides longitudinal evidence that some parental feeding practices influence Mexican American children's weight status, and that children's weight status also influences some parental feeding practices. Feeding practices of both mothers and fathers were related to children's weight status, underscoring the importance of including fathers in research on parental feeding practices and child obesity.


Simulated nitrogen deposition affects wood decomposition by cord-forming fungi.
Anthropogenic nitrogen (N) deposition affects many natural processes, including forest litter decomposition. Saprotrophic fungi are the only organisms capable of completely decomposing lignocellulosic (woody) litter in temperate ecosystems, and therefore the responses of fungi to N deposition are critical in understanding the effects of global change on the forest carbon cycle. Plant litter decomposition under elevated N has been intensively studied, with varying results. The complexity of forest floor biota and variability in litter quality have obscured N-elevation effects on decomposers. Field experiments often utilize standardized substrates and N-levels, but few studies have controlled the decay organisms. Decomposition of beech (Fagus sylvatica) blocks inoculated with two cord-forming basidiomycete fungi, Hypholoma fasciculare and Phanerochaete velutina, was compared experimentally under realistic levels of simulated N deposition at Wytham Wood, Oxfordshire, UK. Mass loss was greater with P. velutina than with H. fasciculare, and with N treatment than in the control. Decomposition was accompanied by growth of the fungal mycelium and increasing N concentration in the remaining wood. We attribute the N effect on wood decay to the response of cord-forming wood decay fungi to N availability. Previous studies demonstrated the capacity of these fungi to scavenge and import N to decaying wood via a translocating network of mycelium. This study shows that small increases in N availability can increase wood decomposition by these organisms. Dead wood is an important carbon store and habitat. The responses of wood decomposers to anthropogenic N deposition should be considered in models of forest carbon dynamics.


Holocene woodlands in the southwestern deserts.
Twenty-nine radiocarbon-dated pack rat middens document woodland communities in the deserts of the southwestern United States less than 10,000 years ago. A synchronous change from woodland to desert or grassland occurred about 8000 years ago in the Chihuahuan, Sonoran, and Mohave deserts. A shift of the Aleutian low and the winter storm track to the north, which resulted in drastically reduced winter precipitation in these areas, is inferred. The shift to nonpluvial climates in the Southwest lagged behind the beginning of nonglacial climates in the North because the melting continental glaciers contined to affect general circulation patterns.


Having a word with yourself: neural correlates of self-criticism and self-reassurance.
Self-criticism is strongly correlated with a range of psychopathologies, such as depression, eating disorders and anxiety. In contrast, self-reassurance is inversely associated with such psychopathologies. Despite the importance of self-judgements and evaluations, little is known about the neurophysiology of these internal processes. The current study therefore used a novel fMRI task to investigate the neuronal correlates of self-criticism and self-reassurance. Participants were presented statements describing two types of scenario, with the instruction to either imagine being self-critical or self-reassuring in that situation. One scenario type focused on a personal setback, mistake or failure, which would elicit negative emotions, whilst the second was of a matched neutral event. Self-criticism was associated with activity in lateral prefrontal cortex (PFC) regions and dorsal anterior cingulate (dAC), therefore linking self-critical thinking to error processing and resolution, and also behavioural inhibition. Self-reassurance was associated with left temporal pole and insula activation, suggesting that efforts to be self-reassuring engage similar regions to expressing compassion and empathy towards others. Additionally, we found a dorsal/ventral PFC divide between an individual's tendency to be self-critical or self-reassuring. Using multiple regression analyses, dorsolateral PFC activity was positively correlated with high levels of self-criticism (assessed via self-report measure), suggesting greater error processing and behavioural inhibition in such individuals. Ventrolateral PFC activity was positively correlated with high self-reassurance. Our findings may have implications for the neural basis of a range of mood disorders that are characterised by a preoccupation with personal mistakes and failures, and a self-critical response to such events.


Preventing Hospitalization with Veterans Affairs Home-Based Primary Care: Which Individuals Benefit Most?
To examine how medical complexity modifies the relationship between enrollment in Department of Veterans Affairs (VA) home-based primary care (HBPC) and hospitalization for ambulatory care-sensitive conditions (ACSC) for veterans with diabetes mellitus and whether the effect of HBPC on hospitalizations varies according to clinical condition. Retrospective cohort study. VA and non-VA hospitals. VA beneficiaries aged 67 and older with diabetes mellitus and enrolled in Medicare (N = 364,972). Instrumental variables regression models were used to estimate the effect of HBPC enrollment on hospitalization for ACSCs (defined according to the Agency for Healthcare Research and Quality Prevention Quality Indicators) overall and in subgroups stratified according to medical complexity. Models were also estimated for each ACSC to determine which conditions were most sensitive to HBPC. Distance from the veteran's residence to the nearest HBPC site was used as the instrumental variable. HBPC was associated with fewer ACSC hospitalizations (odds ratio (OR) = 0.35 per person-month, 95% confidence interval (CI) = 0.30-0.42). For veterans in the highest quartile of medical complexity, HBPC enrollment was associated with fewer ACSC hospitalizations (OR = 0.43, 95% CI = 0.19-0.93), whereas for those in the lowest quartile, HBPC was associated with more ACSC hospitalizations (OR = 33.2, 95% CI = 4.6-240.1). HBPC enrollment was associated with fewer hospitalizations for a range of ACSCs. HBPC enrollment was associated with fewer hospitalizations for a range of ACSCs in veterans with diabetes mellitus but only in the most medically complex individuals. This demonstrates the importance of appropriate targeting and suggests that the effect of HBPC is attributable to its comprehensive approach rather than condition-specific interventions.


No Evidence That Articulatory Rehearsal Improves Complex Span Performance.
It is usually assumed that articulatory rehearsal improves verbal working memory. Complex span is the most used paradigm to assess working memory functioning; yet, we still lack knowledge about how participants rehearse in this task, and whether these rehearsals are beneficial. In Experiment 1, we investigated the patterns of naturally occurring overt rehearsals in a complex span task requiring processing of a non-verbal distractor task. For comparison, another group of participants completed a matched simple span task with an unfilled delay in between the memoranda. Time permitting, participants rehearsed the memory list in forward serial order, a strategy known as cumulative rehearsal. The degree of cumulative rehearsal was correlated with recall accuracy in both span tasks. Rehearsal frequency was, however, reduced in complex span compared to simple span. To assess the causal role of rehearsal in complex span, we trained a group of participants in a cumulative rehearsal strategy in Experiment 2. This instruction substantially increased the prevalence of cumulative rehearsals compared to a control group. However, the increase in cumulative rehearsal did not translate into an increase in recall accuracy. Our results provide further evidence that rehearsal does not benefit working memory performance.


Unconditional quantum teleportation
Quantum teleportation of optical coherent states was demonstrated experimentally using squeezed-state entanglement. The quantum nature of the achieved teleportation was verified by the experimentally determined fidelity Fexp = 0.58 +/- 0.02, which describes the match between input and output states. A fidelity greater than 0.5 is not possible for coherent states without the use of entanglement. This is the first realization of unconditional quantum teleportation where every state entering the device is actually teleported.


Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing.
The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration.


Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.
One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer. Cancer Immunol Res; 6(5); 509-16. ©2018 AACR.


Oncologic Safety of Prophylactic Nipple-Sparing Mastectomy in a Population With BRCA Mutations: A Multi-institutional Study.
Nipple-sparing mastectomy (NSM) offers superior cosmetic outcomes and has been gaining wide acceptance; however, its role among patients with BRCA mutations remains controversial. To report on the oncologic safety of NSM and provide evidence-based data to patients and health care professionals regarding preservation of the nipple-areolar complex during a risk-reducing mastectomy in a population with BRCA mutations. We retrospectively reviewed the outcomes of 9 institutions' experience with prophylactic NSM from 1968 to 2013 in a cohort of patients with BRCA mutations. Patients with breast cancer were included if they underwent contralateral risk-reducing mastectomy; however, only the prophylactic side was considered in the analysis. Patients found to have an occult primary breast cancer at the time of risk-reducing mastectomy, those having variant(s) of unknown significance, and those undergoing free nipple grafts were excluded. The primary outcome measure was development of a new breast cancer after risk-reducing NSM. Three reference data sources were used to model the expected number of events, and this was compared with our observed number of events. A total of 548 risk-reducing NSMs in 346 patients were performed at 9 institutions. The median age at NSM was 41 years (interquartile range, 34.5-47.5 years). Bilateral prophylactic NSMs were performed in 202 patients (58.4%), and 144 patients (41.6%) underwent a unilateral risk-reducing NSM secondary to cancer in the contralateral breast. Overall, 201 patients with BRCA1 mutations and 145 with BRCA2 mutations were included. With median and mean follow-up of 34 and 56 months, respectively, no ipsilateral breast cancers occurred after prophylactic NSM. Breast cancer did not develop in any patients undergoing bilateral risk-reducing NSMs. Using risk models for BRCA1/2 mutation carriers, approximately 22 new primary breast cancers were expected without prophylactic NSM. Prophylactic NSM resulted in a significant reduction in breast cancer events (test of observed vs expected events, P < .001). Nipple-sparing mastectomies are highly preventive against breast cancer in a BRCA population. Although the follow-up remains relatively short, NSM should be offered as a breast cancer risk-reducing strategy to appropriate patients with BRCA mutations.


Synthesis, oxidation chemistry and cytotoxicity studies on ferrocene derivatives of diethylstilbestrol.
A series of compounds is described in which one of the ethyl groups in diethylstilbestrol has been replaced by a ferrocenyl substituent. Only those derivatives incorporating phenol moieties underwent isomerisation from the Z to the E form, and some of them could be chemically oxidized to a quinone species. The compounds were less cytotoxic against hormone-independent MDA-MB-231 breast cancer cell lines than their corresponding ferrocenyl phenyl or phenol isomers in which the ferrocene and ethyl moieties are linked to the same carbon atom. The biochemical results were evaluated in conjunction with information obtained from electrochemical and chemical oxidation experiments.


Training memory self-efficacy in the chronic stage after stroke: a randomized controlled trial.
Stroke patients with a low memory self-efficacy (MSE) report more memory complaints than patients with a high MSE. The aim of this study was to examine the effect of a memory-training program on MSE in the chronic phase after stroke and to identify which patients benefit most from the MSE training program. In a randomized controlled trial, the effectiveness of the MSE training program (experimental group) was compared with a peer support program (control group) in chronic stroke patients. The primary outcome was MSE, measured using the Metamemory-In-Adulthood Questionnaire. Secondary outcomes included depression, quality of life, and objective verbal memory capacity. Changes in outcomes over the intervention period were compared between both groups. Demographic and clinical variables were studied as potential predictors of MSE outcome in the experimental group. In total, 153 patients were included: mean age = 58 years (standard deviation [SD] = 9.7), 54.9% male, and mean of 54 months (SD = 37) after stroke. Of these, 77 were assigned to the training and 76 to the control group. Improvement of MSE (B = 0.40; P = .019) was significantly greater in the training than in the control group. No significant differences were found for the secondary outcomes. An increase in MSE after training was predicted by a younger age (B = -0.033; P = .006) and a better memory capacity (B = 0.043; P = .009), adjusted for baseline MSE. MSE can be improved by the MSE training program for stroke patients. Younger patients and patients with a better memory capacity benefit most from the MSE training program (Dutch Trial Register: NTR-TC 1656).


Differential flap dynamics in l,d-transpeptidase2 from mycobacterium tuberculosis revealed by molecular dynamics.
Despite the advances in tuberculosis treatment, TB is still one the most deadly infectious diseases and remains a major global health quandary. Mycobacterium tuberculosis (Mtb) is the only known mycobacterium with a high content of 3→3 crosslinks in the biosynthesis of peptidoglycan, which is negligible in most bacterial species. An Mtb lacking LdtMt2 leads to alteration of the colony morphology and loss of virulence which makes this enzyme an attractive target. Regardless of the vital role of LdtMt2 for cell wall survival, the impact of ligand binding on the dynamics of the β-hairpin flap is still unknown. Understanding the structural and dynamical behaviour of the flap regions provides clear insight into the design of the effective inhibitors against LdtMt2. Carbapenems, an specific class of β-lactam family, have been shown to inactivate this enzyme. Herein a comprehensive investigation of the flap dynamics of LdtMt2 complex with substrate and three carbapenems namely, ertapenem, imipenem and meropenem is discussed and analyzed for the first account using 140 ns molecular dynamics simulations. The structural features (RMSD, RMSF and Rg) derived by MD trajectories were analyzed. Distance analysis, particularly tip-tip SER135-ASN167 index, identified conformational changes in terms of flap opening and closure within binding process. Principal component analysis (PCA) was employed to qualitatively understand the divergent effects of different inhibitors on the dominant motion of each residue. To probe different internal dynamics induced by ligand binding, dynamic cross-correlation marix (DCCM) analysis was used. The binding free energies of the selected complexes were assessed using MM-GBSA method and per residue free energy decomposition analysis were performed to characterize the contribution of the key residues to the total binding free energies.


Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors.
GABA(A) (gamma-aminobutyric-acid A) and dopamine D1 and D5 receptors represent two structurally and functionally divergent families of neurotransmitter receptors. The former comprises a class of multi-subunit ligand-gated channels mediating fast interneuronal synaptic transmission, whereas the latter belongs to the seven-transmembrane-domain single-polypeptide receptor superfamily that exerts its biological effects, including the modulation of GABA(A) receptor function, through the activation of second-messenger signalling cascades by G proteins. Here we show that GABA(A)-ligand-gated channels complex selectively with D5 receptors through the direct binding of the D5 carboxy-terminal domain with the second intracellular loop of the GABA(A) gamma2(short) receptor subunit. This physical association enables mutually inhibitory functional interactions between these receptor systems. The data highlight a previously unknown signal transduction mechanism whereby subtype-selective G-protein-coupled receptors dynamically regulate synaptic strength independently of classically defined second-messenger systems, and provide a heuristic framework in which to view these receptor systems in the maintenance of psychomotor disease states.