Colorado's New Proxy Law: Moving from Statute to Guidelines.
In 2016, the Colorado legislature passed an amendment to Colorado's medical proxy law that established a process for the appointment of a physician to act as proxy decision maker of last resort for an unrepresented patient (Colorado HB 16-1101: Medical Decisions For Unrepresented Patients). The legislative process brought together a diverse set of stakeholders, not all of whom supported the legislation. Following passage of the statutory amendment, the Colorado Collaborative for Unrepresented Patients (CCUP), a group of advocates responsible for initiating the legislative process, coordinated a unique effort to engage these stakeholders in the creation of a set of voluntary guidelines to assist facilities and individual careproviders in the implementation of policies and procedures enabled by the statute. This article delineates the questions and concerns of stakeholders, describes how those issues were addressed within the guidelines, and proposes additional opportunities for research to assess the impact of the legislation in Colorado.


Population genomic signatures of divergent adaptation, gene flow and hybrid speciation in the rapid radiation of Lake Victoria cichlid fishes.
Adaptive radiations are an important source of biodiversity and are often characterized by many speciation events in very short succession. It has been proposed that the high speciation rates in these radiations may be fuelled by novel genetic combinations produced in episodes of hybridization among the young species. The role of such hybridization events in the evolutionary history of a group can be investigated by comparing the genealogical relationships inferred from different subsets of loci, but such studies have thus far often been hampered by shallow genetic divergences, especially in young adaptive radiations, and the lack of genome-scale molecular data. Here, we use a genome-wide sampling of SNPs identified within restriction site-associated DNA (RAD) tags to investigate the genomic consistency of patterns of shared ancestry and adaptive divergence among five sympatric cichlid species of two genera, Pundamilia and Mbipia, which form part of the massive adaptive radiation of cichlids in the East African Lake Victoria. Species pairs differ along several axes: male nuptial colouration, feeding ecology, depth distribution, as well as the morphological traits that distinguish the two genera and more subtle morphological differences. Using outlier scan approaches, we identify signals of divergent selection between all species pairs with a number of loci showing parallel patterns in replicated contrasts either between genera or between male colour types. We then create SNP subsets that we expect to be characterized to different extents by selection history and neutral processes and describe phylogenetic and population genetic patterns across these subsets. These analyses reveal very different evolutionary histories for different regions of the genome. To explain these results, we propose at least two intergeneric hybridization events (between Mbipia spp. and Pundamilia spp.) in the evolutionary history of these five species that would have lead to the evolution of novel trait combinations and new species.


Identification, molecular characterization, and experimental transmission of a new hemoplasma isolate from a cat with hemolytic anemia in Switzerland.
Recently, there has been a growing interest in hemotropic mycoplasmal species (also known as the hemoplasmas), the causative agents of infectious anemia in several mammalian species. In felids, two different hemoplasma species have been recognized: Mycoplasma haemofelis (formerly Haemobartonella felis) and "Candidatus Mycoplasma haemominutum." Recently developed molecular methods have allowed sensitive and specific identification and quantification of these agents in feline blood samples. In applying these methods to an epidemiological study surveying the Swiss pet cat population for hemoplasma infection, we discovered a third novel and unique feline hemoplasma isolate in a blood sample collected from a cat that had exhibited clinical signs of severe hemolytic anemia. This agent was readily transmitted via intravenous inoculation to two specific-pathogen-free cats. One of these cats was immunocompromised by the administration of methylprednisolone acetate prior to inoculation, and this cat developed severe anemia. The other immunocompetent cat showed a moderate decrease in packed cell volume. Additionally, an increase in red blood cell osmotic fragility was observed. Sequencing of the entire 16S rRNA gene of the new hemoplasma isolate and phylogenetic analysis showed that the isolate was most closely related to two rodent hemotropic mycoplasmal species, M. coccoides and M. haemomuris. A quantitative real-time PCR assay specific for this newly discovered agent was developed, which will be a prerequisite for the diagnosis of infections with the new hemoplasma isolate.


FANCD2 limits replication stress and genome instability in cells lacking BRCA2.
The tumor suppressor BRCA2 plays a key role in genome integrity by promoting replication-fork stability and homologous recombination (HR) DNA repair. Here we report that human cancer cells lacking BRCA2 rely on the Fanconi anemia protein FANCD2 to limit replication-fork progression and genomic instability. Our results identify a new role of FANCD2 in limiting constitutive replication stress in BRCA2-deficient cells, thereby affecting cell survival and treatment responses.


Radiographic signs of non-venous placement of intended central venous catheters in children.
Central venous catheters (CVCs) are commonly used in children, and inadvertent arterial or extravascular cannulation is rare but has potentially serious complications. To identify the radiographic signs of arterial placement of CVCs. We retrospectively reviewed seven cases of arterially malpositioned CVCs on chest radiograph. These cases were identified through departmental quality-assurance mechanisms and external consultation. Comparison of arterial cases was made with 127 age-matched chest radiographs with CVCs in normal, expected venous location. On each anteroposterior (AP) radiograph we measured the distance of the catheter tip from the right lateral border of the thoracic spine, and the angle of the vertical portion of the catheter relative to the midline. On each lateral radiograph we measured the angle of the vertical portion of each catheter relative to the anterior border of the thoracic spine. When bilateral subclavian catheters were present, the catheter tips were described as crossed, overlapping or uncrossed. On AP radiographs, arterially placed CVCs were more curved to the left, with catheter tip positions located farther to the left of midline than normal venous CVCs. When bilateral, properly placed venous catheters were present, all catheters crossed at the level of the superior vena cava (SVC). When one of the bilateral catheters was in arterial position, neither of the catheters crossed or the inter-catheter crossover distance was exaggerated. On lateral radiographs, there was a marked anterior angulation of the vertical portion of the catheter (mean angle 37 ± 15° standard deviation [SD] in arterial catheters versus 5.9 ± 8.3° SD in normally placed venous catheters). Useful radiographic signs suggestive of unintentional arterial misplacement of vascular catheters include leftward curvature of the vertical portion of the catheter, left-side catheter tip position, lack of catheter crossover on the frontal radiograph, as well as exaggerated anterior angulation of the catheter on the lateral chest radiograph.


Legislating tolerance: Spain's national public smoking law.
While Spain's national tobacco control legislation prohibits smoking in many indoor public places, the law provides for an exception to the prohibition of smoking by allowing separate seating sections and ventilation options in certain public places such as bars and restaurants, hotels and airports. Accordingly, Spain's law is not aligned with Article 8 Guidelines of the World Health Organization's Framework Convention on Tobacco Control, which requires parties to ensure universal protection against secondhand smoke exposure in all enclosed public places, workplaces and on all means of public transport. Spain's law is currently being promoted by the tobacco companies in other countries as a model for smoke-free legislation. In order to prevent weakening of smoke-free laws in other countries through industry-supported exceptions, we investigated the tactics used by the tobacco companies before the implementation of the new law and assessed the consequences of these actions in the hospitality sector. Internal tobacco industry documents made public through US litigation settlements dating back to the 1980s were searched in 2008-9. Documents show that tobacco companies sought to protect hospitality venues from smoking restrictions by promoting separate seating for smokers and ineffective ventilation technologies, supporting an unenforceable voluntary agreement between the Madrid local government and the hospitality industry, influencing ventilation standards setting and manipulating Spanish media. The Spanish National Assembly should adopt comprehensive smoke-free legislation that does not accommodate the interests of the tobacco industry. In doing so, Spain's smoke-free public places law would be better aligned with the Framework Convention on Tobacco Control.


The effects of intrinsic vasopressin on urinary aquaporin-2 excretion and urine osmolality during surgery under general anesthesia.
A radioimmunoassay has been established to measure urinary aquaporin-2 excretion (u-AQP2). To elucidate how u-AQP2 changes when endogenous vasopressin is increased independently of plasma osmolality, we estimated u-AQP2 during general anesthesia for surgery. We collected urine and blood samples from 50 patients before and 90 and 180 min after anesthetic induction. Plasma (29.1+/-12.6 pg/mL) and urinary (565.1+/-207.0 ng/gCr) vasopressin levels were markedly increased after anesthetic induction. Although no significant alteration of plasma osmolality or serum sodium concentration was observed during 180 min, u-AQP2 was significantly increased (preinduction 224.5+/-24.2 fmol/ mgCr; 90 min 243.3+/-31.8; 180 min 331.4+/-45.9), paralleling an increase of plasma and urinary vasopressin. The plasma vasopressin concentration after anesthetic induction was far in excess of that expected based on plasma osmolality. Individual plasma and urinary vasopressin concentrations correlated significantly with u-AQP2. At 180 min after anesthesia, plasma osmolality did not change, but urine osmolality decreased despite increased u-AQP2, and a preanesthetic positive correlation between urine osmolality and u-AQP2 disappeared. Thus, although u-AQP2 correlates with increased intrinsic vasopressin levels, the increase in u-AQP2 did not directly contribute to urine concentration. Apparently, an escape from the physiologic effects of high vasopressin level occurs during anesthesia via a mechanism independent of aquaporin-2. We conclude that the anesthetic would interfere with the urinary concentrating capacity at the level of AQP2-action. The excessive increase of intrinsic vasopressin exactly augmented urinary aquaporin-2 excretion, resulting in urine concentration; however, anesthesia seemed to modify this process possibly by interfering with the aquaporin-2 action.


Making Meaning Together: Embodied Narratives in a Case of Severe Autism.
Shared understanding is generated between individuals before speech through a language of body movement and non-verbal vocalisation, expression of feeling and interest made in gestures of movement and voice. Human understanding is co-created in these embodied projects, displayed in serially organised expressions with shared timing of reciprocal actions between partners. These develop in narrative events that build over cycles of reciprocal expressive action in a four-part structure shared by all the time-based arts: "introduction," "development," "climax," and "conclusion." Pre-linguistic narrative establishes the foundation of later, linguistic intelligence. Yet, participating in social interactions that give rise to narrative development is a central problem of autism spectrum disorder. In this paper, we examine the rapid growth of narrative meaning-making between a non-verbal young woman with severe autism and her new therapist. Episodes of embodied, shared understanding were enabled through a basic therapeutic mode of reciprocal, creative mirroring of expressive gesture. These developed through reciprocal cycles and as the relationship progressed, complete co-created narratives were formed resulting in shared joy and the mutual interest and trust of companionship. These small, embodied stories enabled moments of co-regulated arousal that the young woman had previous difficulty with. These data provide evidence for an intact capacity for non-verbal narrative meaning-making in autism.


The bee tree of life: a supermatrix approach to apoid phylogeny and biogeography.
Bees are the primary pollinators of angiosperms throughout the world. There are more than 16,000 described species, with broad variation in life history traits such as nesting habitat, diet, and social behavior. Despite their importance as pollinators, the evolution of bee biodiversity is understudied: relationships among the seven families of bees remain controversial, and no empirical global-level reconstruction of historical biogeography has been attempted. Morphological studies have generally suggested that the phylogeny of bees is rooted near the family Colletidae, whereas many molecular studies have suggested a root node near (or within) Melittidae. Previous molecular studies have focused on a relatively small sample of taxa (~150 species) and genes (seven at most). Public databases contain an enormous amount of DNA sequence data that has not been comprehensively analysed in the context of bee evolution. We downloaded, aligned, concatenated, and analysed all available protein-coding nuclear gene DNA sequence data in GenBank as of October, 2011. Our matrix consists of 20 genes, with over 17,000 aligned nucleotide sites, for over 1,300 bee and apoid wasp species, representing over two-thirds of bee genera. Whereas the matrix is large in terms of number of genes and taxa, there is a significant amount of missing data: only ~15% of the matrix is populated with data. The placement of the root as well as relationships between Andrenidae and other bee families remain ambiguous, as several alternative maximum-likelihood estimates fall within the statistically credible set. However, we recover strong bootstrap support for relationships among many families and for their monophyly. Ancestral geographic range reconstruction suggests a likely origin of bees in the southern hemisphere, with Melittidae ancestrally located within Africa, and Halictidae, Colletidae, and Apidae within the New World. Our study affirms the monophyly of each bee family, sister-taxa relationships between Apidae and Megachilidae (the 'long-tongued bees'), between Colletidae and Stenotritidae, and between Colletidae + Stenotritidae and Halictidae. Our analyses reject a Colletidae-basal hypothesis for family-level relationships and instead support Melittidae as sister to the remaining bees. Southern hemisphere vicariance likely played an important role in early diversification within many bee families.


Topical use of tranexamic acid in primary total knee arthroplasty: a comparative study.
Perioperative blood management represents a major issue in knee arthroplasty. The aim of the present observational study is to compare two different methods of topical tranexamic acid (TXA) administration (periarticular and intraarticular) in primary knee arthroplasty. The present is an observational comparative study. A total of 66 consecutive patients receiving topical injection of TXA after unilateral primary knee arthroplasty due to osteoarthritis were recorded. Patients were divided into two groups: group 1; periarticular injection of TXA and group 2; intraarticular injection. Transfusion rate in group 1 was found to be 15%, compared to 44% in group 2 (p-value= 0.015). In transfused patients the mean received blood units were 1.2 (SD=0.44) in group 1, compared to 1.06 (SD=0.24; p-value=0.34) in group 2. The mean hospital stay of group 1 patients was 7.94 days (SD=2.79), compared to 9.58 days (SD=3.26; p-value=0.03) in group 2. The main findings of the study are that statically significant higher transfusion rates, as well as longer in-hospital stay were found in the intraarticular group, when compared to the periarticular group. According to these two parameters the present study has shown that the topical periarticular TXA injection is superior to the intraarticular one. Further research is of utmost importance in order to conclude to the optimum combination of knee arthroplasty perioperative blood management.


A visual sense of number.
Evidence exists for a nonverbal capacity for the apprehension of number, in humans [1] (including infants [2, 3]) and in other primates [4-6]. Here, we show that perceived numerosity is susceptible to adaptation, like primary visual properties of a scene, such as color, contrast, size, and speed. Apparent numerosity was decreased by adaptation to large numbers of dots and increased by adaptation to small numbers, the effect depending entirely on the numerosity of the adaptor, not on contrast, size, orientation, or pixel density, and occurring with very low adaptor contrasts. We suggest that the visual system has the capacity to estimate numerosity and that it is an independent primary visual property, not reducible to others like spatial frequency or density of texture [7].


An assessment of emergency department information systems based on the HL7 functional profile.
Emergency Department Information System (EDIS) plays a significant role in supporting the emergency department (ED) workflow. Hence, it is vital to assess the services provided by this system in order to identify its strengths and weaknesses. The study aimed to assess the information systems in use in the ED of 11 teaching hospitals associated with Isfahan University of Medical Sciences (IUMS) so as to identify their strengths and weaknesses and improving the quality of these systems. This study was conducted using descriptive-applied research method. Data collection tool was a checklist developed based on EDIS functional profile. It covered two sections of the profile, namely direct care and supportive functions and their respective subsections. Data were analyzed using descriptive statistics through the estimation of the frequency and frequency percentage for each respective section and subsections using SPSS software v. 20. The content conformance rate of the information systems in use in the EDs of IUMS' teaching hospitals was found to be 49.72% and 75.25% for the direct care section and supportive functions section, respectively. In addition, the overall conformance rate in the hospitals surveyed was up to 53.15%. As per the findings of this study, it is suggested that some important clinical and administrative functions should be incorporated into the redesigned information systems in use in the EDs under study.


An Analysis of the Influence of Noneffective Instructions in Linear Genetic Programming.
Linear Genetic Programming (LGP) represents programs as sequences of instructions and has a Directed Acyclic Graph (DAG) dataflow. The results of instructions are stored in registers that can be used as arguments by other instructions. Instructions that are disconnected from the main part of the program are called noneffective instructions, or structural introns. They also appear in other DAG-based GP approaches like Cartesian Genetic Programming (CGP). This article studies four hypotheses on the role of structural introns: noneffective instructions (1) serve as evolutionary memory, where evolved information is stored and later used in search, (2) preserve population diversity, (3) allow neutral search, where structural introns increase the number of neutral mutations and improve performance, and (4) serve as genetic material to enable program growth. We study different variants of LGP controlling the influence of introns for symbolic regression, classification, and digital circuits problems. We find that there is (1) evolved information in the noneffective instructions that can be reactivated and that (2) structural introns can promote programs with higher effective diversity. However, both effects have no influence on LGP search performance. On the other hand, allowing mutations to not only be applied to effective but also to noneffective instructions (3) increases the rate of neutral mutations and (4) contributes to program growth by making use of the genetic material available as structural introns. This comes along with a significant increase of LGP performance, which makes structural introns important for LGP.


A "Wear and Tear" Hypothesis to Explain Sudden Infant Death Syndrome.
Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures.


Imaging Laser-Induced Choroidal Neovascularization in the Rodent Retina Using Optical Coherence Tomography Angiography.
The purpose of this study was to evaluate the performance of optical coherence tomography angiography (OCTA) in visualizing laser-induced choroidal neovascularization (CNV) in the rodent retina. Choroidal neovascularization was induced via laser photocoagulation in 2 male Brown Norway rats and 2 male C57BL/6 mice. For qualitative comparison, the animals were imaged in vivo with OCTA, indocyanine green angiography (ICGA), and fluorescein angiography (FA), and ex vivo with immunofluorescence confocal microscopy, 14 days post laser photocoagulation without anti-vascular endothelial growth factor (anti-VEGF) intervention. For longitudinal quantitative analysis, CNV was induced in 6 additional male C57BL/6 mice. Three mice intravitreally received an anti-VEGF agent and the remaining 3 mice phosphate buffered saline (PBS) vehicle 7 days post laser photocoagulation. These animals were imaged using OCTA 6, 14, and 21 days post laser photocoagulation. The area and volume of the laser-induced CNV lesions were measured longitudinally. In both mice and rats, OCTA qualitatively showed high correlation with FA, ICGA, and immunofluorescence imaging. Unlike FA and ICGA, which does not show the microvasculature due to dye leakage, OCTA visualized the CNV microvasculature with resolution and contrast comparable to immunofluorescence images. Longitudinal imaging enabled normalization of the CNV area and volume, reducing inherent variation in the CNV size. By using only 3 mice in each group, statistically significant differences (P < 0.01) in the CNV area and volume could be demonstrated. Optical coherence tomography angiography enables noninvasive visualization of the laser-induced CNV microvasculature in the rodent retina with high resolution and tissue-lumen contrast, providing quantifiable in vivo measurements for longitudinal analysis.


Brief history of agricultural systems modeling.
Agricultural systems science generates knowledge that allows researchers to consider complex problems or take informed agricultural decisions. The rich history of this science exemplifies the diversity of systems and scales over which they operate and have been studied. Modeling, an essential tool in agricultural systems science, has been accomplished by scientists from a wide range of disciplines, who have contributed concepts and tools over more than six decades. As agricultural scientists now consider the "next generation" models, data, and knowledge products needed to meet the increasingly complex systems problems faced by society, it is important to take stock of this history and its lessons to ensure that we avoid re-invention and strive to consider all dimensions of associated challenges. To this end, we summarize here the history of agricultural systems modeling and identify lessons learned that can help guide the design and development of next generation of agricultural system tools and methods. A number of past events combined with overall technological progress in other fields have strongly contributed to the evolution of agricultural system modeling, including development of process-based bio-physical models of crops and livestock, statistical models based on historical observations, and economic optimization and simulation models at household and regional to global scales. Characteristics of agricultural systems models have varied widely depending on the systems involved, their scales, and the wide range of purposes that motivated their development and use by researchers in different disciplines. Recent trends in broader collaboration across institutions, across disciplines, and between the public and private sectors suggest that the stage is set for the major advances in agricultural systems science that are needed for the next generation of models, databases, knowledge products and decision support systems. The lessons from history should be considered to help avoid roadblocks and pitfalls as the community develops this next generation of agricultural systems models.


Effect of methotrexate on serum levels of IL-22 in patients with psoriasis.
Interleukin-22 (IL-22) is the effector molecule of T-helper subset 22 (Th-22) lineage that promotes keratinocyte proliferation and dermal inflammation in psoriasis. Methotrexate is widely used as a first-line treatment in moderate to severe psoriasis. Methotrexate inhibits inflammatory and cytokinetic processes via various mechanisms, but the relevance of these to psoriasis is limited and whether methotrexate is specifically able to down-regulate Th22 cytokines is unknown. To determine if methotrexate reduces IL-22 in cases of psoriasis. Nineteen patients with moderate to severe psoriasis were given methotrexate 15 mg per week for up to 12 weeks. Serum levels of IL-22 were determined by enzyme-linked immunosorbent assay (ELISA) before and after treatment. Eleven of 19 patients (57.8%) achieved a 75% PASI score reduction. IL-22 levels were significantly higher in untreated psoriasis patients (56.63 ± 60.73 pg/mL) than in controls (12.58 ± 12.59 pg/mL). Methotrexate significantly reduced serum levels of IL-22 in psoriasis patients to 5.91 ± 7.97 pg/mL (p<0.001). Moreover, there was a significant positive correlation between IL-22 levels and PASI (r=0.63, p=0.004). Methotrexate significantly reduces serum IL-22 levels in cases of psoriasis. This is a novel mechanism by which methotrexate acts in the treatment of this disease.


Knowledge of obstetric danger signs and birth preparedness practices among women in rural Uganda.
Improving knowledge of obstetric danger signs and promoting birth preparedness practices are strategies aimed at enhancing utilization of skilled care in low-income countries. The aim of the study was to explore the association between knowledge of obstetric danger signs and birth preparedness among recently delivered women in south-western Uganda. The study included 764 recently delivered women from 112 villages in Mbarara district. Community survey methods were used and 764 recently delivered women from 112 villages in Mbarara district were included in study. Interviewer administered questionnaire were used to collect data. Logistic regression analyses were conducted to explore the relationship between knowledge of key danger signs and birth preparedness. Fifty two percent of women knew at least one key danger sign during pregnancy, 72% during delivery and 72% during postpartum. Only 19% had knowledge of 3 or more key danger signs during the three periods. Of the four birth preparedness practices; 91% had saved money, 71% had bought birth materials, 61% identified a health professional and 61% identified means of transport. Overall 35% of the respondents were birth prepared. The relationship between knowledge of at least one key danger sign during pregnancy or during postpartum and birth preparedness showed statistical significance which persisted after adjusting for probable confounders (OR 1.8, 95% CI: 1.2-2.6) and (OR 1.9, 95% CI: 1.2-3.0) respectively. Young age and high levels of education had synergistic effect on the relationship between knowledge and birth preparedness. The associations between knowledge of at least one key danger sign during childbirth or knowledge that prolonged labour was a key danger sign and birth preparedness were not statistically significant. The prevalence of recently delivered women who had knowledge of key danger signs or those who were birth prepared was very low. Since the majority of women attend antenatal care sessions, the quality and methods of delivery of antenatal care education require review so as to improve its effectiveness. Universal primary and secondary education programmes ought to be promoted so as to enhance the impact of knowledge of key danger signs on birth preparedness practices.


First characterisation of two important postulated intermediates in the formation of a HydT DNA lesion, a thymidine oxidation product.
A number of environmental pollutants and endogenous oxidation agents form 1-(2-deoxy-β-d-ribofuranosyl)-5-hydroxy-5-methylhydantoin (HydT), an important DNA lesion resulting from thymidine oxidation. In this paper, two intermediates, postulated in the formation of HydT, have been characterised for the first time. The first, N1-formyl-N3-pyruvoylurea intermediate, was produced by the ozonolysis reaction of 2',3',5'-tri-O-acetylribo-, 3',5'-di-O-TBS- and N3,O3',O5-tribenzyl-protected thymidines and was shown to produce, upon decomposition and depending on the protecting group and the conditions, HydT alone, or together with protected-β-d-ribofuranosyl-N1-formylurea and formamide products. In addition, the second and long sought, open-chain-pyruvoylurea intermediate, was produced through de novo synthesis in protected β-d-ribofuranosyl-, 2-deoxy-β-d-ribofuranosyl- and 2-deoxy-β-d-ribopyranosyl systems. The conditions that induce the cyclization to the hydantoin ring of HydT have been determined. The chemistry utilised in the de novo synthesis is suitable for generating isotopically labelled HydT, as a reference in isotope-dilution-aided quantification of DNA damage.


Reliability analysis and optimization of the consensus docking approach for the development of virtual screening studies.
Ligand-protein docking is one of the most common techniques used in virtual screening campaigns. Despite the large number of docking software available, there is still the need of improving the efficacy of docking-based virtual screenings. To date, only very few studies evaluated the possibility of combining the results of different docking methods to achieve higher success rates in virtual screening studies (consensus docking). In order to better understand the range of applicability of this approach, we carried out an extensive enriched database analysis using the DUD dataset. The consensus docking protocol was then refined by applying modifications concerning the calculation of pose consensus and the combination of docking methods included in the procedure. The results obtained suggest that this approach performs as well as the best available methods found in literature, confirming the idea that this procedure can be profitably used for the identification of new hit compounds.


NHC-coordinated silagermenylidene functionalized in allylic position and its behaviour as a ligand.
Vinylidenes are common in transition metal chemistry with catalytic applications in alkene and alkyne metathesis. We report here the isolation of a heavier analogue of vinylidene, an α-chlorosilyl functionalized silagermenylidene stabilized by an N-heterocyclic carbene (NHC). Silagermenylidene (Tip2Cl)Si-(Tip)Si=Ge·NHC(iPr2Me2) (4-E/Z; Tip = 2,4,6-(i)Pr3C6H2; NHC(iPr2Me2) = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) is available as an E/Z-equilibrium mixture from Tip2Si=Si(Tip)Li and NHC(iPr2Me2)·GeCl2. Reaction of 4-E/Z with Fe2(CO)9 affords a silagermenylidene Fe(CO)4 complex, which slowly isomerizes to its E-isomer at 25 °C. A rearranged Fe(CO)3 complex with an allylic SiGeSi ligand is obtained as a side product at 65 °C.


Impaired rich club connectivity in unaffected siblings of schizophrenia patients.
Schizophrenia has been conceptualized as a disorder of brain connectivity. Recent studies suggest that brain connectivity may be disproportionally impaired among the so-called rich club. This small core of densely interconnected hub regions has been hypothesized to form an important infrastructure for global brain communication and integration of information across different systems of the brain. Given the heritable nature of the illness, we hypothesized that connectivity disturbances, including abnormal rich club connectivity, may be related to familial vulnerability for schizophrenia. To test this hypothesis, both schizophrenia patients and unaffected siblings of patients were investigated. Rich club organization was examined in networks derived from diffusion-weighted imaging in 40 schizophrenia patients, 54 unaffected siblings of patients, and 51 healthy control subjects. Connectivity between rich club hubs was differentially reduced across groups (P = .014), such that it was highest in controls, intermediate in siblings (7.9% reduced relative to controls), and lowest in patients (19.6% reduced compared to controls). Furthermore, in patients, lower levels of rich club connectivity were found to be related to longer duration of illness and worse overall functioning. Together, these findings suggest that impaired rich club connectivity is related to familial, possibly reflecting genetic, vulnerability for schizophrenia. Our findings support a central role for abnormal rich club organization in the etiology of schizophrenia.


CIDP and other inflammatory neuropathies in diabetes - diagnosis and management.
Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes.


Food Industry Donations to Academic Programs: A Cross-Sectional Examination of the Extent of Publicly Available Data.
No studies have documented the prevalence of the food industry's funding of academic programs, which is problematic because such funding can create conflicts of interest in research and clinical practice. We aimed to quantify the publicly available information on the food industry's donations to academic programs by documenting the amount of donations given over time, categorizing the types of academic programs that receive food industry donations, cataloguing the source of the donation information, and identifying any stated reasons for donations. Researchers cataloged online data from publicly available sources (e.g., official press releases, news articles, tax documents) on the food industry's donations to academic programs from 2000 to 2016. Companies included 26 food and beverage corporations from the 2016 Fortune 500 list in the United States. Researchers recorded the: (1) monetary value of the donations; (2) years the donations were distributed; (3) the name and type of recipient; (4) source of donation information; and (5) reasons for donations. Adjusting for inflation, we identified $366 million in food industry donations (N = 3274) to academic programs. Universities received 45.2% (n = 1480) of donations but accounted for 67.9% of total dollars given in the sample. Community colleges, schools (i.e., preschool, elementary, middle, and high schools), and academic nonprofits, institutes, foundations, and research hospitals collectively received 54.8% of the donations, but made up less than one-third of the monetary value of donations. Half of the donations (49.0%) did not include a stated reason for the donation. In our sample, donations grew from $3 million in 2000 to $24 million in 2016. Food companies in our sample donated millions of dollars to universities and other academic programs but disclosed little information on the purpose of the donations. Achieving transparency in donation practices may only be possible if federal policies begin to require disclosures or if companies voluntarily disclose information.


Strigolactones: a plant phytohormone as novel anti-inflammatory agents.
Strigolactones (SLs) are a novel class of plant hormones with enormous potential for the prevention and treatment of inflammation. To further investigate the anti-inflammatory activities of SLs, a representative SL, GR24, and the reductive products of its D-ring were synthesized and their anti-inflammatory activities were fully evaluated on both in vitro and in vivo models. Among these compounds, the two most active optical isomers (2a and 6a) demonstrated strong inhibitory activity on the release of inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) by blocking the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways; they also greatly inhibited the migration of neutrophils and macrophages in fluorescent protein labeled zebrafish larvae. These results identified the promising anti-inflammatory effects of SLs, and suggested that both the absolute configuration of SL and the α,β-unsaturated D-ring structure are essential for the observed anti-inflammatory activity.


Influence of primary sedimentation on pre-denitrification system performances.
The effects of suppressing primary sedimentation on nitrogen removal efficiency of a pre-denitrification system have been evaluated for a large municipal wastewater treatment plant. Simulations have been carried out using the STOAT model. For both the process schemes with and without primary sedimentation, nitrification efficiencies are calculated for increasing influent loads of COD, total N and suspended solids. The sensitivity analysis shows that for the usual carbon to nitrogen ratios in the raw influent both the process schemes allow the requested removal efficiencies, whereas for significantly high C/N ratios the scheme with primary sedimentation is preferable.


Expression of angiogenic basic fibroblast growth factor, platelet derived growth factor, thrombospondin-1 and their receptors at the porcine maternal-fetal interface.
Commercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid-gestation. Although an exact mechanism for this loss is not known, deficits in vasculature at the attachment sites appear to be a major cause. We hypothesized that a balance between pro-angiogenic and anti-angiogenic factors is needed at the maternal-fetal interface for successful conceptus development. Six selected members of the pro-angiogenic fibroblast growth factor (FGF) and platelet derived growth factor (PDGF) families and anti-angiogenic factor thrombospondin-1 (TSP-1) and its receptor CD36 were quantified and localized at the porcine maternal-fetal interface at early and midgestation time points. Mesometrial endometrium was collected from non-pregnant gilts (n = 8). Endometrial and chorioallantoic membrane samples were collected from healthy and arresting conceptus attachment sites at gestation day (gd) 20 (n = 8) and gd 50 (n = 8). At gd20 arresting conceptus attachment sites were distinguished by decreased vasculature of the placental membranes and decreased conceptus size. At gd50 arresting conceptuses attachment sites were identified by smaller conceptus length and weight measurements. Quantitative real time PCR was used to determine relative transcript levels of genes of interest, and cellular localization was determined by immunohistochemistry in paraffin embedded endometrial sections. At gd20, endometrial samples from arresting conceptuses had elevated transcripts for bFGF, and PDGF-bb than healthy sites (p < 0.05). At gd50, bFGF, FGFR2, and CD36 were more abundant at arresting than at healthy conceptus attachment sites (p < 0.05). Chorioallantoic membrane from arresting conceptus attachment sites at gd20 had elevated transcripts for bFGF, FGFR1, FGFR2 and CD36 compared with healthy sites (p < 0.05). FGFR2 transcripts were more abundant in chorioallantoic membrane from arresting conceptuses at gd 50 (p < 0.05). Immunohistochemical localization of selected pro- and anti-angiogenic factors and receptors revealed their abundance in the luminal epithelium, uterine glands and perivascular areas of endometrium at gd20 and gd50. We provide comprehensive analysis of pro and anti-angiogenic factors at the porcine maternal fetal interface during early and mid-pregnancy. At mRNA levels, the majority of pro-angiogenic factors investigated were elevated at the sites of fetal arrest. These observations contrast with our previous findings of decreased Vascular Endothelial Growth Factor (VEGF) family members at arresting sites, and suggest that the bFGF family functions as a compensatory survival mechanism when major angiogenic proteins are decreasing at the sites of fetal arrest.


Multiple antibiotic changes during the first 72 hours of hospitalization.
Increasing concern about inappropriate antibiotic use prompted us to examine whether our patients were receiving frequent and perhaps unwarranted changes of antibiotic therapy. We evaluated antibiotic prescribing by the physicians in the Emergency Department and by those on the inpatient medical service during the first 72 hours of hospitalization in 119 patients admitted with suspected serious infections to an acute care, university-affiliated, municipal teaching hospital. The appropriateness of antibiotic prescriptions was assessed independently and retrospectively by 2 infectious disease specialists (each based at a different hospital) using a 4-grade scale (from 1 = wrong choice to 4 = appropriate). Of their evaluations of the 427 antibiotic regimens given to the 119 patients during 4 defined intervals during their first 72 hours of hospitalization, 90% agreed with each other within 1 grade. Their evaluations were then compared with the selections that had been made at each interval by the prescribing physicians. Successive prescribing physicians changed the antibiotic regimens in 77% of cases during the first 24 hours and in 56% during the next 48, often without apparent clinical or microbiologic indications. By 72 hours, the 119 patients had received a mean of 3.1 +/- 1.3 (+/-SD) different antibiotics, and 40 received between 4 and 7. Only 7% of the patients had no change in the regimen prescribed originally. Many patients had multiple changes of antibiotics, often unnecessarily, resulting in exposure to too many agents.


Towards a safe non-invasive method for evaluating the carbonate substitution levels of hydroxyapatite (HAP) in micro-calcifications found in breast tissue.
A new diagnostic concept based on deep Raman spectroscopy is proposed permitting the non-invasive determination of the level of carbonate substitution in type II calcifications (HAP). The carbonate substitution has shown to be directly associated with the pathology of the surrounding breast tissue and different pathology groups can therefore be separated using specific features in the Raman spectra of the calcifications. This study explores the principle of distinguishing between type II calcifications, found in proliferating lesions, by using the strongest Raman peak from calcium hydroxyapatites (the phosphate peak at 960 cm(-1)) to act as a surrogate marker for carbonate substitution levels. It is believed that carbonate ion substitution leads to a perturbation of the hydroxyapatite lattice which in turn affects the phosphate vibrational modes. By studying calcifications, with known carbonate content, buried in porcine tissue it has been possible to evaluate the feasibility of using the proposed approach to probe the composition of the calcifications in vivo and hence provide pathology specific information non-invasively, in real time. Using the proposed concept we were able to determine the level of carbonate substitutions through soft tissue phantom samples (total thickness of 5.6 mm). As the level of carbonate substitution has been previously correlated with mid-FTIR to the lesion type, i.e. whether benign or invasive or in situ carcinoma, the new findings provide a major step forward towards establishing a new capability for diagnosing benign and malignant lesions in breast tissue in a safe and non-invasive manner in vivo.


Thrombelastography is better than PT, aPTT, and activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, hemorrhagic shock and resuscitation in pigs.
Hypothermia and hemorrhagic shock contribute to coagulopathy after trauma. In this study, we investigated the independent and combined effects of hypothermia and hemorrhage with resuscitation on coagulation in swine and evaluated clinically relevant tests of coagulation. Pigs (n = 24) were randomized into four groups of six animals each: sham control, hypothermia, hemorrhage with resuscitation, and hypothermia, hemorrhage with resuscitation combined. Hypothermia to 32 degrees C was induced with a cold blanket. Hemorrhage was induced by bleeding 35% of total blood volume followed by resuscitation with lactated Ringer's solution. Coagulation was assessed by thrombin generation, prothrombin time (PT), activated partial thromboplastin time (aPTT), activated clotting time (ACT), and thrombelastography (TEG) from blood samples taken at baseline and 4 hour after hypothermia and/or hemorrhage with resuscitation. Data were compared with analysis of variance. Baseline values were similar among groups. There were no changes in any measurements in the control group. Compared with baseline values, hemorrhage with resuscitation increased lactate to 140% +/- 15% (p < 0.05). Hypothermia decreased platelets to 73% +/- 3% (p < 0.05) with no effect on fibrinogen. Hemorrhage with resuscitation reduced platelets to 72% +/- 4% and fibrinogen to 71% +/- 3% (both p < 0.05), with similar decreases in platelets and fibrinogen observed in the combined group. Thrombin generation was decreased to 75% +/- 4% in hypothermia, 67% +/- 6% in hemorrhage with resuscitation, and 75% +/- 10% in the combined group (all p < 0.05). There were no significant changes in PT or aPTT by hemorrhage or hypothermia. ACT was prolonged to 122% +/- 1% in hypothermia, 111% +/- 4% in hemorrhage with resuscitation, and 127% +/- 3% in the combined group (all p < 0.05). Hypothermia prolonged the initial clotting time (R) and clot formation time (K), and decreased clotting rapidity (alpha) (all p < 0.05). Hemorrhage with resuscitation only decreased clot strength (maximum amplitude [MA], p < 0.05). TEG parameters in the combined group reflected the abnormal R, K, MA, and alpha observed in the other groups. Hypothermia inhibited clotting times and clotting rate, whereas hemorrhage impaired clot strength. Combining hypothermia with hemorrhage impaired all these clotting parameters. PT, aPTT were not sensitive whereas ACT was not specific in detecting these coagulation defects. Only TEG differentiated mechanism related to clotting abnormalities, and thus may allow focused treatment of clotting alterations associated with hypothermia and hemorrhagic shock.


What are fair study benefits in international health research? Consulting community members in Kenya.
Planning study benefits and payments for participants in international health research in low- income settings can be a difficult and controversial process, with particular challenges in balancing risks of undue inducement and exploitation and understanding how researchers should take account of background inequities. At an international health research programme in Kenya, this study aimed to map local residents' informed and reasoned views on the effects of different levels of study benefits and payments to inform local policy and wider debates in international research. Using a relatively novel two-stage process community consultation approach, five participatory workshops involving 90 local residents from diverse constituencies were followed by 15 small group discussions, with components of information-sharing, deliberation and reflection to situate normative reasoning within debates. Framework Analysis drew inductively and deductively on voice-recorded discussions and field notes supported by Nvivo 10 software, and the international research ethics literature. Community members' views on study benefits and payments were diverse, with complex contextual influences and interplay between risks of giving 'too many' and 'too few' benefits, including the role of cash. While recognising important risks for free choice, research relationships and community values in giving 'too many', the greatest concerns were risks of unfairness in giving 'too few' benefits, given difficulties in assessing indirect costs of participation and the serious consequences for families of underestimation, related to perceptions of researchers' responsibilities. Providing benefits and payments to participants in international research in low-income settings is an essential means by which researchers meet individual-level and structural forms of ethical responsibilities, but understanding how this can be achieved requires a careful account of social realities and local judgment. Concerns about undue inducement in low-income communities may often be misplaced; we argue that greater attention should be placed on avoiding unfairness, particularly for the most-poor.


High attrition among HIV-infected patients with advanced disease treated in an intermediary referral center in Maputo, Mozambique.
In Mozambique, antiretroviral therapy (ART) scale-up has been successfully implemented. However, attrition in care remains a major programmatic challenge. In 2009, an intermediary-level HIV referral center was created in Maputo to ensure access to specialized care for HIV-infected patients with complications (advanced clinical-immunological stage, Kaposi sarcoma, or suspected ART failure). To determine the attrition from care and to identify risk factors that lead to high attrition among patients referred to an intermediary-level HIV referral center. This was a retrospective cohort study from 2009 to 2011. A total of 1,657 patients were enrolled, 847 (51%) were men, the mean age was 36 years (standard deviation: 11), the mean CD4 count was 27 cells/µl (interquartile range: 11-44), and one-third were severely malnourished. The main reasons for referral were advanced clinical stages (WHO stages 3 and 4, and CD4 count <50 cells/µl) in 70% of the cases, and 19% had Kaposi sarcoma. The overall attrition rate was 28.7 per 100 person-years (PYs) - the mortality rate was 5.0 (95% confidence interval [CI]: 4.2-5.9) per 100 PYs, and the loss-to-follow-up rate was 23.7 (95% CI: 21.9-25.6) per 100 PYs. There were 793 attritions - 137 deaths and 656 lost to follow-up (LTFU); 77% of all attrition happened within the first year. The factors independently associated with attrition were male sex (adjusted hazard ratio [aHR]: 1.15, 95% CI: 1.0-1.3), low body mass index (aHR: 1.51, 95% CI: 1.2-1.8), WHO clinical stage 3 or 4 (aHR: 1.30, 95% CI: 1.0-1.6; and aHR: 1.91, 95% CI: 1.4-2.5), later year of enrollment (aHR 1.61, 95% CI 1.3-1.9), and 'being already on ART' at enrollment (aHR 13.71, 95% CI 11.4-16.4). Attrition rates among HIV-infected patients enrolled in an intermediary referral center were high, mainly related to advanced stage of clinical disease. Measures are required to address this, including innovative strategies for HIV-testing uptake, earlier ART initiation and nutritional supplementation, and special attention to men and those who are already on ART at enrolment. Qualitative research is required to understand the reasons for being LTFU and design informed evidence-based interventions.


Liver microsomes; an integrated morphological and biochemical study.
Rat liver, liver homogenates, and microsome fractions separated therefrom were examined systematically in the electron microscope in sections of OsO(4)-fixed, methacrylate-embedded tissue and pellets. It was found that most microsomes are morphologically identical with the rough surfaced elements of the endoplasmic reticula of hepatic cells. They appear as isolated, membrane-bound vesicles, tubules, and cisternae which contain an apparently homogeneous material of noticeable density, and bear small, dense particles (100 to 150 A) attached to their outer aspect. In solutions of various osmolar concentrations they behave like osmometers. The findings suggest that they derive from the endoplasmic reticulum by a generalized pinching-off process rather than by mechanical fragmentation. The microsome fractions contain in addition relatively few vesicles free of attached particles, probably derived from the smooth surfaced parts of the endoplasmic reticula. Dense, peribiliary bodies represent a minor component of the same fractions. The microsomes derived from 1 gm. wet weight liver pulp contained (averages of 10 experiments) 3.09 mg. protein N, 3.46 mg. RNA (RNA/protein N = 1.12), and 487 microg. phospholipide P. They displayed DPNH-cytochrome c reductase activity and contained an alcohol-soluble hemochromogen. The microsome preparations proved resistant to washing and "aging." Treatment with versene and incubation with ribonuclease (30 minutes at 37 degrees C.) resulted in appreciable losses of RNA and in partial or total disappearance of attached particles. Treatment with deoxycholate (0.3 to 0.5 per cent, pH = 7.5) induced a partial clarification of the microsome suspensions which, upon centrifugation, yielded a small pellet of conglomerated small, dense particles (100 to 150 A) with only occasionally interspersed vesicles. The pellet contained approximately 80 to 90 per cent of the RNA and approximately 20 per cent of the protein N of the original microsomes. The supernatant accounted satisfactorily for the materials lost during deoxycholate treatment. The findings suggest that the microsomal RNA is associated with the small particles whereas most of the protein and nearly all of the phospholipide, hemochromogen, and DPNH-cytochrome c reductase activity are associated with the membrane or content of the microsomes.


Utility of repeat cytological assessment of thyroid nodules initially classified as benign: clinical insights from multidisciplinary care in an Irish tertiary referral centre.
Fine needle aspiration biopsy (FNAB) is the tool of choice for evaluating thyroid nodules with the majority classified as benign following initial assessment. However, concern remains about false negative results and some guidelines have recommended routine repeat aspirates. We aimed to assess the utility of routine repeat FNAB for nodules classified as benign on initial biopsy and to examine the impact of establishing a multidisciplinary team for the care of these patients. We performed a retrospective review of 400 consecutive patients (413 nodules) who underwent FNAB of a thyroid nodule at our hospital between July 2008 and July 2011. Data recorded included demographic, clinical, histological and radiological variables. Three hundred and fifty seven patients (89 %) were female. Median follow-up was 5.5 years. Two hundred and fifty eight (63 %) nodules were diagnosed as benign. The rate of routine repeat biopsy increased significantly over the time course of the study (p for trend = 0.012). Nine Thy 2 nodules were classified differently on the basis of routine repeat biopsy; one patient was classified as malignant on repeat biopsy and was diagnosed with papillary thyroid carcinoma. Eight were classified as a follicular lesions on repeat biopsy-six diagnosed as benign following lobectomy; two declined lobectomy and were followed radiologically with no nodule size increase. The false negative rate of an initial benign cytology result, from a thyroid nodule aspirate, is low. In the setting of an experienced multidisciplinary thyroid team, routine repeat aspiration is not justified.


Exposure to oral bisphosphonates and risk of esophageal cancer.
Use of oral bisphosphonates has increased dramatically in the United States and elsewhere. Esophagitis is a known adverse effect of bisphosphonate use, and recent reports suggest a link between bisphosphonate use and esophageal cancer, but this has not been robustly investigated. To investigate the association between bisphosphonate use and esophageal cancer. Data were extracted from the UK General Practice Research Database to compare the incidence of esophageal and gastric cancer in a cohort of patients treated with oral bisphosphonates between January 1996 and December 2006 with incidence in a control cohort. Cancers were identified from relevant Read/Oxford Medical Information System codes in the patient's clinical files. Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals for risk of esophageal and gastric cancer in bisphosphonate users compared with nonusers, with adjustment for potential confounders. Hazard ratio for the risk of esophageal and gastric cancer in the bisphosphonate users compared with the bisphosphonate nonusers. Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. Excluding patients with less than 6 months' follow-up, there were 41 826 members in each cohort (81% women; mean age, 70.0 (SD, 11.4) years). One hundred sixteen esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. The incidence of esophageal and gastric cancer combined was 0.7 per 1000 person-years of risk in both the bisphosphonate and control cohorts; the incidence of esophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1000 person-years of risk, respectively. There was no difference in risk of esophageal and gastric cancer combined between the cohorts for any bisphosphonate use (adjusted hazard ratio, 0.96 [95% confidence interval, 0.74-1.25]) or risk of esophageal cancer only (adjusted hazard ratio, 1.07 [95% confidence interval, 0.77-1.49]). There also was no difference in risk of esophageal or gastric cancer by duration of bisphosphonate intake. Among patients in the UK General Practice Research Database, the use of oral bisphosphonates was not significantly associated with incident esophageal or gastric cancer.


Prevalence of amyotrophic lateral sclerosis - United States, 2010-2011.
Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease for which no cure has been identified. Although ALS has no known definitive cause, familial ALS (a hereditary form) occurs in 5%-10% of cases. Many hypotheses have been formulated about what causes ALS, including chemical exposures, occupational exposure, military service, infectious agents, nutritional intake, physical activity, and trauma. Worldwide, ALS affects white males aged >60 years more often than any other group. In the United States, ALS surveillance is necessary to estimate the incidence and prevalence of ALS and collect data on risk factors. ALS is not a nationally notifiable condition in the United States (i.e., it is not a reportable condition in all jurisdictions), and individual state reporting requirements differ, with Massachusetts being the only state that mandates reporting. October 19, 2010-December 31, 2011. In 2009, the federal Agency for Toxic Substances and Disease Registry (ATSDR) implemented the National ALS Registry to collect and analyze data regarding persons with ALS in the United States. The main goals of the Registry, as defined by the 2008 ALS Registry Act, are to describe the incidence and prevalence of ALS better, examine risk factors such as environmental and occupational exposures, and characterize the demographics of those living with ALS. The Registry uses a two-pronged approach to identify all cases of ALS. The first approach uses four existing national administrative databases (maintained by Medicare, Medicaid, the Veterans Health Administration, and the Veterans Benefits Administration) to identify prevalence of ALS. The second approach uses a secure web portal (http://www.cdc.gov/als) that was launched to the public on October 19, 2010, to identify cases not included in the four national administrative databases and to collect risk-factor data on known ALS cases. ALS patients who have registered via the web portal can complete brief risk-factor surveys online that are intended to attain a better understanding of ALS (e.g., genetics and environmental and occupational exposures) and help determine disease progression. During October 19, 2010-December 31, 2011, a total of 12,187 persons meeting the surveillance case definition of definite ALS were identified by the Registry, for a prevalence of 3.9 cases of ALS per 100,000 persons in the U.S. general population. Incidence cannot be measured because the date of diagnosis was not noted in all patient records. Overall, ALS was more common among white males, non-Hispanics, and persons aged 60-69 years. The age groups with the lowest number of persons with ALS were age 18-39 years and age >80 years. Males had a higher prevalence rate of ALS than females overall and across all data sources. This is the first (and to date the only) effort to estimate the national prevalence of ALS in the United States. Using the combined approach of the national databases and the web-based portal enables researchers to estimate ALS prevalence more accurately. Registry findings for the prevalence of ALS are consistent with findings from long-established ALS registries in Europe and from smaller-scale epidemiologic studies conducted previously in the United States. Although incidence cannot be measured with Registry data at this time, incidence is being measured in smaller geographic areas that have participated in ATSDR's State and Metropolitan Area ALS surveillance projects. Data collected by the National ALS Registry are being used to better describe the prevalence of ALS in the United States and to help facilitate research. The combined approach of using national administrative databases and a self-enrollment web portal to collect data is novel and potentially could be used for other non-notifiable diseases such as Parkinson's disease or multiple sclerosis. ATSDR is working closely with ALS advocacy and support groups, researchers, health-care professionals, and others to promote the National ALS Registry in order to capture all cases of ALS. To further enhance and strengthen the Registry, ATSDR is 1) adding new modules to the portal to examine other potential risk factors, 2) launching a feasibility study for a novel ALS biorepository (available at http://wwwn.cdc.gov/als/ALSBioRegistry.aspx) linked to the Registry that would potentially provide biologic specimens from patient enrollees to help researchers learn more about disease etiology, 3) engaging in surveillance activities in selected states and large metropolitan areas to help test the completeness of the Registry as well as calculating incidence in these areas, and 4) using the Registry to recruit patient enrollees for new clinical trials and epidemiologic studies. Additional information about the National ALS Registry is available at http://www.cdc.gov/als or by calling toll-free at 1-877-442-9719.


National health spending in 2013: growth slows, remains in step with the overall economy.
In 2013 US health care spending increased 3.6 percent to $2.9 trillion, or $9,255 per person. The share of gross domestic product devoted to health care spending has remained at 17.4 percent since 2009. Health care spending decelerated 0.5 percentage point in 2013, compared to 2012, as a result of slower growth in private health insurance and Medicare spending. Slower growth in spending for hospital care, investments in medical structures and equipment, and spending for physician and clinical care also contributed to the low overall increase.


Prolonged display or rapid internalization of the IgG-binding protein ZZ anchored to the surface of cells using the diphtheria toxin T domain.
We have shown previously that the diphtheria toxin transmembrane domain (T) may function as a membrane anchor for soluble proteins fused at its C-terminus. Binding to membranes is triggered by acidic pH. Here, we further characterized this anchoring device. Soluble proteins may be fused at the N-terminus of the T domain or at both extremities, without modifying its membrane binding properties. This allows one to choose the orientation of the protein to be attached to the membrane. Maximum binding to the cell surface is reached within 1 h. Anchoring occurs on cells previously treated with proteinase K, suggesting that T interacts with the lipid phase of the membrane without the help of cell surface proteins. Binding does not permeabilize cells or affect cell viability, despite the fact that it permeabilizes liposomes and alters their structure. When attached to L929 fibroblasts, the proteins are not internalized and remain displayed at their surface for more than 24 h. When bound to K562 myeloid cells, the molecules are internalized and degraded. Thus, depending on the cell type, soluble proteins may be anchored to the surface of cells by the T domain for an extended time or directed towards an internalization pathway.


Hidden hazards of SARS-CoV-2 transmission in hospitals: A systematic review.
Despite their considerable prevalence, dynamics of hospital-associated COVID-19 are still not well understood. We assessed the nature and extent of air- and surface-borne SARS-CoV-2 contamination in hospitals to identify hazards of viral dispersal and enable more precise targeting of infection prevention and control. PubMed, ScienceDirect, Web of Science, Medrxiv, and Biorxiv were searched for relevant articles until June 1, 2021. In total, 51 observational cross-sectional studies comprising 6258 samples were included. SARS-CoV-2 RNA was detected in one in six air and surface samples throughout the hospital and up to 7.62 m away from the nearest patients. The highest detection rates and viral concentrations were reported from patient areas. The most frequently and heavily contaminated types of surfaces comprised air outlets and hospital floors. Viable virus was recovered from the air and fomites. Among size-fractionated air samples, only fine aerosols contained viable virus. Aerosol-generating procedures significantly increased (ORair = 2.56 (1.46-4.51); ORsurface = 1.95 (1.27-2.99)), whereas patient masking significantly decreased air- and surface-borne SARS-CoV-2 contamination (ORair = 0.41 (0.25-0.70); ORsurface = 0.45 (0.34-0.61)). The nature and extent of hospital contamination indicate that SARS-CoV-2 is likely dispersed conjointly through several transmission routes, including short- and long-range aerosol, droplet, and fomite transmission.


Impressive Radiation Stability of Organic Solar Cells Based on Fullerene Derivatives and Carbazole-Containing Conjugated Polymers.
We explored the radiation stability of carbazole-based electron-donor conjugated polymers, acceptor fullerene derivative [60]PCBM, and their blends as active layer components of organic solar cells. An exposure to γ rays induced evident degradation effects in bulk samples of the pristine fullerene acceptor ([60]PCBM) and two investigated electron-donor conjugated polymers: PCDTBT and PCDTTBTBTT. The most severe radiation damage occurred in [60]PCBM as can be concluded from the significant losses in open circuit voltage, fill factor, and efficiency of photovoltaic (PV) devices comprising the exposed fullerene acceptor. Conjugated polymers PCDTBT and PCDTTBTBTT showed substantially different radiation stabilities: the samples of PCDTTBTBTT exposed to 200 Gy lost ∼25% of their nominal photovoltaic efficiency due to a substantial decay of all device parameters, while PCDTBT alone showed just a minor aging under the same conditions. The fullerene-polymer composites were much more resistant with respect to the radiation damage than the bulk samples of pristine materials. In particular, the PCDTBT/[60]PCBM composite films demonstrated an outstanding radiation stability while maintaining more than 80% of the initial photovoltaic efficiency after exposure to γ rays with a maximum absorbed dose of 6500 Gy. Considering an average annual radiation dose of 160 Gy according to the NASA estimations for satellites at geocentric Earth orbits, organic solar cells based on PCDTBT/[60]PCBM blends hold a promise to deliver lifetimes well above 10 years. The revealed impressive radiation stability of PCDTBT/[60]PCBM blends in combination with other advantages of organic solar cells, for example, their mechanical flexibility and lightweight, points to a bright future of this PV technology in space industry applications.


Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model.
The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.


Updates and five-year evaluation of the S.A.F.E. program: a family psychoeducational program for serious mental illness.
This brief report reviews recent updates to the S.A.F.E. Program, a family psychoeducational intervention for serious mental illness created in the Veterans Affairs (VA) system. The improvements and significant content additions to the curriculum are outlined. Further, positive five-year program evaluation data are described, including high levels of participant retention and satisfaction. Program attendance is positively correlated with understanding of mental illness, awareness of VA resources, and ability to engage in self-care activities-and inversely correlated with caregiver distress. This data lays the groundwork for a randomized clinical trial and raises questions about the necessity of diagnostic-specific family programming.


Utilization of supportive care by survivors of colorectal cancer: results from the PROFILES registry.
In an equitable healthcare system, healthcare utilization should be predominantly explained by patient-perceived need and clinical need factors. This study aims to analyze whether predisposing, enabling, and need factors are associated with the utilization of supportive care (i.e., dietary care, oncological nursing care, physical therapy, psychological care, or participation in a rehabilitation program consisting of an exercise component and a psycho-educational component) among survivors of colorectal cancer in the Netherlands. Cross-sectional data of 3957 survivors of colorectal cancer (1-11 years after diagnosis) were used. Clinical data from the Eindhoven Cancer Registry were linked to questionnaire data from the PROFILES registry. Regression analyses were used to examine which predisposing, enabling, and need factors were associated with self-reported utilization of supportive care. Utilization of supportive care was primarily associated with younger age, patient-perceived need (i.e., lower physical health, anxious mood, depressive mood, and fatigue), and clinical need (i.e., tumor stage, radiotherapy, chemotherapy, comorbidity, having a stoma and lower BMI) factors. In the Netherlands, utilization of supportive care by survivors of colorectal cancer is primarily associated with younger age, patient-perceived need, and clinical need factors. Apart from the association with younger age, the utilization of supportive care services seems to be quite equitable. Further research is needed to determine whether there is indeed inequity in the provision of supportive care to older survivors, or whether older survivors are less in need of supportive care.


Modelling shifts in agroclimate and crop cultivar response under climate change.
(i) to identify at national scale areas where crop yield formation is currently most prone to climate-induced stresses, (ii) to evaluate how the severity of these stresses is likely to develop in time and space, and (iii) to appraise and quantify the performance of two strategies for adapting crop cultivation to a wide range of (uncertain) climate change projections. To this end we made use of extensive climate, crop, and soil data, and of two modelling tools: N-AgriCLIM and the WOFOST crop simulation model. N-AgriCLIM was developed for the automatic generation of indicators describing basic agroclimatic conditions and was applied over the whole of Finland. WOFOST was used to simulate detailed crop responses at four representative locations. N-AgriCLIM calculations have been performed nationally for 3829 grid boxes at a 10 × 10 km resolution and for 32 climate scenarios. Ranges of projected shifts in indicator values for heat, drought and other crop-relevant stresses across the scenarios vary widely - so do the spatial patterns of change. Overall, under reference climate the most risk-prone areas for spring cereals are found in south-west Finland, shifting to south-east Finland towards the end of this century. Conditions for grass are likely to improve. WOFOST simulation results suggest that CO2 fertilization and adjusted sowing combined can lead to small yield increases of current barley cultivars under most climate scenarios on favourable soils, but not under extreme climate scenarios and poor soils. This information can be valuable for appraising alternative adaptation strategies. It facilitates the identification of regions in which climatic changes might be rapid or otherwise notable for crop production, requiring a more detailed evaluation of adaptation measures. The results also suggest that utilizing the diversity of cultivar responses seems beneficial given the high uncertainty in climate change projections.


Increased Cell Traction-Induced Prestress in Dynamically Cultured Microtissues.
Prestress is a phenomenon present in many cardiovascular tissues and has profound implications on their in vivo functionality. For instance, the in vivo mechanical properties are altered by the presence of prestress, and prestress also influences tissue growth and remodeling processes. The development of tissue prestress typically originates from complex growth and remodeling phenomena which yet remain to be elucidated. One particularly interesting mechanism in which prestress develops is by active traction forces generated by cells embedded in the tissue by means of their actin stress fibers. In order to understand how these traction forces influence tissue prestress, many have used microfabricated, high-throughput, micrometer scale setups to culture microtissues which actively generate prestress to specially designed cantilevers. By measuring the displacement of these cantilevers, the prestress response to all kinds of perturbations can be monitored. In the present study, such a microfabricated tissue gauge platform was combined with the commercially available Flexcell system to facilitate dynamic cyclic stretching of microtissues. First, the setup was validated to quantify the dynamic microtissue stretch applied during the experiments. Next, the microtissues were subjected to a dynamic loading regime for 24 h. After this interval, the prestress increased to levels over twice as high compared to static controls. The prestress in these tissues was completely abated when a ROCK-inhibitor was added, showing that the development of this prestress can be completely attributed to the cell-generated traction forces. Finally, after switching the microtissues back to static loading conditions, or when removing the ROCK-inhibitor, prestress magnitudes were restored to original values. These findings show that intrinsic cell-generated prestress is a highly controlled parameter, where the actin stress fibers serve as a mechanostat to regulate this prestress. Since almost all cardiovascular tissues are exposed to a dynamic loading regime, these findings have important implications for the mechanical testing of these tissues, or when designing cardiovascular tissue engineering therapies.


Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-alpha in relation to brain edema and contusion following controlled cortical impact injury in rats.
Traumatic brain injury is associated with release of the excitotoxin glutamate and production of pro-inflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha). Following controlled cortical impact injury, cerebrospinal fluid (CSF) glutamate, IL-6, and TNF-alpha concentrations were measured to investigate their relationship to evolving tissue damage. Compared to non-traumatized rats CSF glutamate, IL-6 and TNF-alpha levels were significantly increased by 8 h after trauma (P<0.005). Parallel to increasing brain swelling and contusion CSF glutamate was significantly elevated over time, reaching highest levels by 48 h (33+/-4 microM) while IL-6 and TNF-alpha showed maximum values at 24 h after trauma (42+/-7 and 4.7+/-1 pg/ml) (P<0.005). The observed different temporal profile of CSF glutamate, IL-6, and TNF-alpha following focal traumatic brain injury could be of therapeutic importance.


Protein kinase A signalling in Schistosoma mansoni cercariae and schistosomules.
Cyclic AMP (cAMP)-dependent protein kinase/protein kinase A regulates multiple processes in eukaryotes by phosphorylating diverse cellular substrates, including metabolic and signalling enzymes, ion channels and transcription factors. Here we provide insight into protein kinase A signalling in cercariae and 24h in vitro cultured somules of the blood parasite, Schistosoma mansoni, which causes human intestinal schistosomiasis. Functional mapping of activated protein kinase A using anti-phospho protein kinase A antibodies and confocal laser scanning microscopy revealed activated protein kinase A in the central and peripheral nervous system, oral-tip sensory papillae, oesophagus and excretory system of intact cercariae. Cultured 24h somules, which biologically represent the skin-resident stage of the parasite, exhibited similar activation patterns in oesophageal and nerve tissues but also displayed striking activation at the tegument and activation in a region resembling the germinal 'stem' cell cluster. The adenylyl cyclase activator, forskolin, stimulated somule protein kinase A activation and produced a hyperkinesia phenotype. The biogenic amines, serotonin and dopamine known to be present in skin also induced protein kinase A activation in somules, whereas neuropeptide Y or [Leu(31),Pro(34)]-neuropeptide Y attenuated protein kinase A activation. However, neuropeptide Y did not block the forskolin-induced somule hyperkinesia. Bioinformatic investigation of potential protein associations revealed 193 medium confidence and 59 high confidence protein kinase A interacting partners in S. mansoni, many of which possess putative protein kinase A phosphorylation sites. These data provide valuable insight into the intricacies of protein kinase A signalling in S. mansoni and a framework for further physiological investigations into the roles of protein kinase A in schistosomes, particularly in the context of interactions between the parasite and the host.


Multicore fiber for cold-atomic cloud monitoring.
Thanks to an all solid core photonic crystal fiber (PCF) used as a multicore fiber, we propose and experimentally demonstrate what is to our knowledge a new optical detection scheme for the spontaneous emission collection of cold atoms. A Magneto-Optical Trap (MOT) is placed in front of a polished PCF end-face. As they display a higher optical index than the surrounding cladding silica, the 108 rods (equivalent to a 108 pixels camera) of this PCF are light guiding and behave like an array of detectors. Both global and local properties of the trapped atoms are probed. A MOT lifetime is reported. We also take advantage of the multi-core geometry for a real time detection of the center-of-mass motion of the atomic cloud.


Prognostic value of metabolic tumor volume and total lesion glycolysis assessed by 18F-FDG PET/CT in endometrial cancer.
Surgical staging is the most confidential method for prognosis prediction. However, in which stage the surgery is needed and the treatment management of these patients is controversial. Presentation of new determinant factors with imaging methods for prediction of poor prognosis can provide better disease management. The aim of our study was to demonstrate the ability of metabolic tumor volume and total lesion glycolysis as a prognostic factor to predict the disease-free survival time, necessity of adjuvant radiotherapy-chemotherapy, and the association of these parameters with the clinicopathological features. Forty-four endometrial cancer diagnosed patients whose PET/CT scans were performed for treatment planning were included in our study. Metabolic parameters (SUVmax, metabolic tumor volume, total lesion glycolysis) of the primary tumor were calculated. Abdominal hysterectomy was performed for all patients. Histopathologic findings were noted. Patients were followed for 31.4 ± 14.8 months. Metabolic tumor volume and total lesion glycolysis were significant prognostic factors for disease-free survival, whereas SUVmax did not effect disease-free survival. According to regression analysis, only metabolic tumor volume was found significant for radiotherapy planning (cutoff metabolic tumor volume; 26.30 ml). There was significant association between metabolic tumor volume, total lesion glycolysis and early-stage, myometrial invasion, and lymph node positivity. We observed only weak association between SUVmax and myometrial invasion. ROC curve calculated metabolic tumor volume and total lesion glycolysis cutoff values as 19.6 ml and 90 g for early-stage, 14.3 ml and 173.4 g for myometrial invasion, and 29.7 ml and 283.1 g for lymph node positivity, respectively. Metabolic tumor volume and total lesion glycolysis may be used as prognostic factors for endometrial cancer. The association between SUVmax and clinical findings, disease-free survival, histopathological features are weak. Further studies are needed for demonstrating the prognostic value of metabolic volumetric parameters.


Microwave thermotherapy for benign prostatic hyperplasia.
Transurethral resection of the prostate (TURP) has been the gold-standard treatment for alleviating urinary symptoms and improving urinary flow in men with symptomatic benign prostatic hyperplasia (BPH). However, the morbidity of TURP approaches 20%, and less invasive techniques have been developed for treating BPH. Preliminary data suggest that microwave thermotherapy, which delivers microwave energy to produce coagulation necrosis in prostatic tissue, is a safe, effective treatment for BPH. To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. Randomized controlled trials were identified from The Cochrane Library, MEDLINE, EMBASE, bibliographies of retrieved articles, reviews, technical reports, and by contacting relevant expert trialists and microwave manufacturers. All randomized controlled trials evaluating transurethral microwave thermotherapy (TUMT) for men with symptomatic BPH were eligible for this review. Comparison groups could include transurethral resection of the prostate, minimally invasive prostatectomy techniques, sham thermotherapy procedures, and medications. Outcome measures included urinary symptoms, urinary function, prostate volume, mortality, morbidity, and retreatment. Two review authors independently identified potentially relevant abstracts and then assessed the full papers for inclusion. Two review authors independently abstracted study design, baseline characteristics, and outcomes data and assessed methodological quality using a standard form. We attempted to obtain missing data from authors or sponsors, or both. In this update, we identified no new randomized comparisons of TUMT that provided evaluable effectiveness data. Fifteen studies involving 1585 patients met the inclusion criteria, including six comparisons of microwave thermotherapy with TURP, eight comparisons with sham thermotherapy procedures, and one comparison with an alpha-blocker. Study durations ranged from 3 to 60 months. The mean age of participants was 66.8 years and the baseline symptom scores and urinary flow rates, which did not differ across treatment groups, demonstrated moderately severe lower urinary tract symptoms. The pooled mean urinary symptom scores decreased by 65% with TUMT and by 77% with TURP. The weighted mean difference (WMD) with 95% confidence interval (CI) for the International Prostate Symptom Score (IPSS) was -1.00 (95% CI -2.03 to -0.03), favoring TURP. The pooled mean peak urinary flow increased by 70% with TUMT and by 119% with TURP. The WMD for peak urinary flow was 5.08 mL/s (95% CI 3.88 to 6.28 mL/s), favoring TURP. Compared to TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. Microwave thermotherapy improved IPSS symptom scores (WMD -5.15, 95% CI -4.26 to -6.04) and peak urinary flow (WMD 2.01 mL/s, 95% CI 0.85 to 3.16) compared with sham procedures. Microwave thermotherapy also improved IPSS symptom scores (WMD -4.20, 95% CI -3.15 to -5.25) and peak urinary flow (WMD 2.30 mL/s, 95% CI 1.47 to 3.13) in the one comparison with alpha-blockers. No studies evaluated the effects of symptom duration, patient characteristics, prostate-specific antigen levels, or prostate volume on treatment response. Microwave thermotherapy techniques are effective alternatives to TURP and alpha-blockers for treating symptomatic BPH in men with no history of urinary retention or previous prostate procedures and prostate volumes between 30 to 100 mL. However, TURP provided greater symptom score and urinary flow improvements and reduced the need for subsequent BPH treatments compared to TUMT. Small sample sizes and differences in study design limit comparisons between devices with different designs and energy levels. The effects of symptom duration, patient characteristics, or prostate volume on treatment response are unknown.


Transcriptional profiling of XdrA, a new regulator of spa transcription in Staphylococcus aureus.
Transcription of spa, encoding the virulence factor protein A in Staphylococcus aureus, is tightly controlled by a complex regulatory network, ensuring its temporal expression over growth and at appropriate stages of the infection process. Transcriptomic profiling of XdrA, a DNA-binding protein that is conserved in all S. aureus genomes and shares similarity with the XRE family of helix-turn-helix, antitoxin-like proteins, revealed it to be a previously unidentified activator of spa transcription. To assess how XdrA fits into the complex web of spa regulation, a series of regulatory mutants were constructed; consisting of single, double, triple, and quadruple mutants lacking XdrA and/or the three key regulators previously shown to influence spa transcription directly (SarS, SarA, and RNAIII). A series of lacZ reporter gene fusions containing nested deletions of the spa promoter identified regions influenced by XdrA and the other three regulators. XdrA had almost as strong an activating effect on spa as SarS and acted on the same spa operator regions as SarS, or closely overlapping regions. All data from microarrays, Northern and Western blot analyses, and reporter gene fusion experiments indicated that XdrA is a major activator of spa expression that appears to act directly on the spa promoter and not through previously characterized regulators.


Fingerprint of volcanic forcing on the ENSO-Indian monsoon coupling.
Coupling of the El Niño-Southern Oscillation (ENSO) and Indian monsoon (IM) is central to seasonal summer monsoon rainfall predictions over the Indian subcontinent, although a nonstationary relationship between the two nonlinear phenomena can limit seasonal predictability. Radiative effects of volcanic aerosols injected into the stratosphere during large volcanic eruptions (LVEs) tend to alter ENSO evolution; however, their impact on ENSO-IM coupling remains unclear. Here, we investigate how LVEs influence the nonlinear behavior of the ENSO and IM dynamical systems using historical data, 25 paleoclimate reconstructions, last-millennium climate simulations, large-ensemble targeted climate sensitivity experiments, and advanced analysis techniques. Our findings show that LVEs promote a significantly enhanced phase-synchronization of the ENSO and IM oscillations, due to an increase in the angular frequency of ENSO. The results also shed innovative insights into the physical mechanism underlying the LVE-induced enhancement of ENSO-IM coupling and strengthen the prospects for improved seasonal monsoon predictions.


Effects of natalizumab treatment on the cerebrospinal fluid proteome of multiple sclerosis patients.
Natalizumab is a very effective, relatively new drug for the treatment of relapsing remitting multiple sclerosis. Inflammatory and neurodegenerative processes in the central nervous system are presumed to cause adverse effects during the course of this disease. To monitor the effects of natalizumab treatment on the cerebrospinal fluid (CSF) proteome of patients, CSF samples were taken from patients before commencing treatment as well as after 1 year of treatment. Profiling proteomics experiments using electrospray Orbitrap mass spectrometry and pair wise comparison of patients before and after 1 year of natalizumab treatment revealed a number of candidate biomarkers that were significantly differentially abundant between the before and after treatment groups. Three proteins were subsequently validated using selected reaction monitoring (SRM) in a new, independent sample set. All three proteins, Ig mu chain C region and haptoglobin, both known inflammation-related proteins, as well as Chitinase-3-like protein 1, were confirmed by SRM to be significantly lower abundant in CSF of multiple sclerosis patients after 1 year of natalizumab treatment. The findings for Chitinase-3-like protein 1, a presumed biomarker for more rapid progression from a first clinically isolated syndrome to clinically definite multiple sclerosis, was further confirmed by ELISA measurements.


Real-Time Constant Monitoring of Fall Risk Index by Means of Fully-Wireless Insoles.
Constant monitoring of gait in real life conditions is considered the best way to assess Fall Risk Index (FRI) since most falls happen out of the ideal conditions in which clinicians are currently analyzing the patient's behavior. This paper presents the WIISEL platform and results obtained through the use of the first full-wireless insole devices that can measure almost all gait related data directly on the feet (not in the upper part of the body as most existing wearable solutions). The platform consists of a complete tool-chain: insoles, smartphone & app, server & analysis tool, FRI estimation and user access. Results are obtained by combining parameters in a personalized way to build individual fall risk index assessed by experts with the help of data analytics. New FRI has been compared with standards that validate the quality of its prediction in a statistically significant way. That qualitatively relevant information is being provided to the platform users, being either end-users/patients, relatives or caregivers and the related clinicians to ideally assess about their long term evolution.


Interferon α-Enhanced Clearance of Group A Streptococcus Despite Neutropenia.
Neutrophils and monocytes are crucial for controlling bacterial infections. More-frequent bacterial infections are accordingly encountered in neutropenic patients undergoing chemotherapy. This is not the case for pegylated interferon α (IFN-α)-induced neutropenia. We hypothesized that IFN-α induces a compensatory innate antibacterial state that prevents bacterial infections despite the neutropenia. To investigate whether patients with hepatitis C virus infection treated with IFN-α killed group A Streptococcus (GAS) better than before initiating therapy, whole blood was used to perform ex vivo GAS killing assays before, during, and after IFN-α therapy. We found that IFN-α therapy enhanced GAS killing in whole blood ex vivo despite the decreased neutrophil and monocyte numbers during IFN-α therapy. IFN-α also boosted neutrophil- and monocyte-mediated GAS killing in vitro. Underlying mechanisms included increased production of the antibacterial properdin, a regulator of the complement activation, as well as reactive oxygen species. These findings help to explain the rather discrepant facts of neutropenia but preserved antibacterial immune defenses in patients treated with IFN-α.