Genetic Insurance Discrimination in Sudden Arrhythmia Death Syndromes: Empirical Evidence From a Cross-Sectional Survey in North America.
There is virtually no information assessing the insurability of families affected with Sudden Arrhythmia Death Syndromes (SADS) for the determination of the nonclinical implications of genetic screening. It is important to identify the barriers and challenges faced by families as a result of genetic screening for SADS to enable equitable access to insurance coverage. To explore the insurance coverage experiences of SADS-affected families, we administered a cross-sectional online survey across North America from April 28, 2012 to November 13, 2013. Participants included individuals with a SADS diagnosis and their relatives who have applied for insurance (health, life, travel, and disability) or have existing insurance coverage. Of 202 participants, 92% had a SADS diagnosis (92%) as either a proband (50%) or an affected relative (42%); 8% of participants were unaffected family members of a proband; and genetic confirmation was reported by 73%. Of the 54% of SADS respondents who applied for insurance, 60% were rejected by insurers. The preexisting SADS diagnosis was the major reason reported for rejection (57%). Most respondents (80%) had insurance coverage through a spouse/parent plan at the time of diagnosis; 14% experienced a subsequent negative effect on coverage. Thirty-nine percent of affected SADS respondents reported an increase in insurance premium rates. Increased genetic testing has negatively impacted insurability for SADS patients and affected family members. The challenges in obtaining life and health insurance are mainly because of the preexisting condition, even in the presence of protective laws in the United States.


Acceleration and Speed Performance of Brazilian Elite Soccer Players of Different Age-Categories.
This study aimed to compare vertical jump ability (squat-jump [SJ] and countermovement-jump [CMJ]), relative to body mass mean propulsive power in the jump-squat (MPP-REL JS), and the 0-5, 5-10, and 10-20 m acceleration and speed among soccer players from the same professional club, divided into age-categories (U15 [n = 20], U17 [n = 53], U20 [n = 22] and senior [n = 25] players). The tests were performed at the start of the preseason in indoor facilities. The magnitude-based inference approach and the standardized differences (based on effect sizes) were used to compare the age-groups. The SJ, CMJ, and MPP-REL JS increased across the age-groups up to U20, the latter being similar to senior players. Interestingly, the 0-5 m acceleration was likely and possibly higher in U15 players compared to U17 and senior players. Although soccer athletes improve their unloaded and loaded jump abilities across the age-categories (plateauing during adulthood), the same does not hold true for acceleration capacity, from the early phases of players' development (i.e., U15). Strength and conditioning professionals should seek effective strategies to minimize impairment in maximal acceleration performance of elite soccer players throughout their prospective training programs.


The role of city size and urban form in the surface urban heat island.
Urban climate is determined by a variety of factors, whose knowledge can help to attenuate heat stress in the context of ongoing urbanization and climate change. We study the influence of city size and urban form on the Urban Heat Island (UHI) phenomenon in Europe and find a complex interplay between UHI intensity and city size, fractality, and anisometry. Due to correlations among these urban factors, interactions in the multi-linear regression need to be taken into account. We find that among the largest 5,000 cities, the UHI intensity increases with the logarithm of the city size and with the fractal dimension, but decreases with the logarithm of the anisometry. Typically, the size has the strongest influence, followed by the compactness, and the smallest is the influence of the degree to which the cities stretch. Accordingly, from the point of view of UHI alleviation, small, disperse, and stretched cities are preferable. However, such recommendations need to be balanced against e.g. positive agglomeration effects of large cities. Therefore, trade-offs must be made regarding local and global aims.


Prospective analysis of premature mortality in schizophrenia in relation to health service engagement: a 7.5-year study within an epidemiologically complete, homogeneous population in rural Ireland.
While premature death in schizophrenia is well recognised, mortality risk has received little longitudinal study in relation to population representativeness and patient engagement with health services. Within a rural Irish catchment area of socioeconomic, ethnic and geographical homogeneity and low residential mobility, an epidemiologically complete population of 72 patients with schizophrenia was followed up over 7.5 years in order to quantify mortality prospectively. Information was obtained in relation to 99% of the cohort, with 94% of those surviving retained in engagement with psychiatric care. There were 25 deaths (35% of cohort). A relative risk of 2.06 (95% CI, 1.40-2.80; P < 0.001) among this epidemiologically complete population may constitute an estimate of risk for mortality inherent to schizophrenia when disengagement from health services, residential mobility and socioeconomic, ethnic and geographical diversity are minimised. On long-term prospective evaluation, risk for death in schizophrenia was doubled on a background of enduring engagement in psychiatric care with increasing provision of community-based services and introduction of second-generation antipsychotics.


Simple regression models as a threshold for selecting AFLP loci with reduced error rates.
Amplified fragment length polymorphism is a popular DNA marker technique that has applications in multiple fields of study. Technological improvements and decreasing costs have dramatically increased the number of markers that can be generated in an amplified fragment length polymorphism experiment. As datasets increase in size, the number of genotyping errors also increases. Error within a DNA marker dataset can result in reduced statistical power, incorrect conclusions, and decreased reproducibility. It is essential that error within a dataset be recognized and reduced where possible, while still balancing the need for genomic diversity. Using simple regression with a second-degree polynomial term, a model was fit to describe the relationship between locus-specific error rate and the frequency of present alleles. This model was then used to set a moving error rate threshold that varied based on the frequency of present alleles at a given locus. Loci with error rates greater than the threshold were removed from further analyses. This method of selecting loci is advantageous, as it accounts for differences in error rate between loci of varying frequencies of present alleles. An example using this method to select loci is demonstrated in an amplified fragment length polymorphism dataset generated from the North American prairie species big bluestem. Within this dataset the error rate was reduced from 12.5% to 8.8% by removal of loci with error rates greater than the defined threshold. By repeating the method on selected loci, the error rate was further reduced to 5.9%. This reduction in error resulted in a substantial increase in the amount of genetic variation attributable to regional and population variation. This paper demonstrates a logical and computationally simple method for selecting loci with a reduced error rate. In the context of a genetic diversity study, this method resulted in an increased ability to detect differences between populations. Further application of this locus selection method, in addition to error-reducing methodological precautions, will result in amplified fragment length polymorphism datasets with reduced error rates. This reduction in error rate should result in greater power to detect differences and increased reproducibility.


Thermoregulation via Temperature-Dependent PGD2 Production in Mouse Preoptic Area.
Body temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of anterior hypothalamus (POA), with ∼30% of its neurons sensitive to brain temperature change. It is still unknown whether and how these temperature-sensitive neurons are involved in thermoregulation, because for eight decades they have only been identified via electrophysiological recording. By combining single-cell RNA-seq with whole-cell patch-clamp recordings, we identified Ptgds as a genetic marker for temperature-sensitive POA neurons. Then, we demonstrated these neurons' role in thermoregulation via chemogenetics. Given that Ptgds encodes the enzyme that synthesizes prostaglandin D2 (PGD2), we further explored its role in thermoregulation. Our study revealed that rising temperature of POA alters the activity of Ptgds-expressing neurons so as to increase PGD2 production. PGD2 activates its receptor DP1 and excites downstream neurons in the ventral medial preoptic area (vMPO) that mediates body temperature decrease, a negative feedback loop for thermoregulation.


State behaviour and dynamics of self-propelled Brownian squares: a simulation study.
We study the state behaviour of self-propelled and Brownian squares as a function of the magnitude of self-propulsion and density using Brownian dynamics simulations. We find that the system undergoes a transition from a fluid state to phase coexistence with increased self-propulsion and density. Close to the transition we find oscillations of the system between a fluid state and phase coexistence that are caused by the accumulation of forces in the dense phase. Finally, we study the coarsening regime of the system and find super-diffusive behaviour.


Vitamin D receptor and growth inhibition by 1,25-dihydroxyvitamin D3 in human malignant melanoma cell lines.
The expression of vitamin D receptors (VDR) and growth inhibition induced by 1,25-dihydroxyvitamin D3 have been noted in certain human malignant melanoma cell lines. In this study, widely disparate levels of VDR mRNA expression were demonstrated in a panel of eight human malignant melanoma cell lines. Quantitation of receptor level by ligand binding assay showed a similar pattern. Proliferation and growth curve analysis was performed in two cell lines: RPMI 7951 (high VDR) and SK-MEL-28 (low VDR). Significant growth inhibition was noted in RPMI 7951 cells at 10(-9) M 1,25-dihydroxyvitamin D3. SK-MEL-28 cells, which express much lower levels of VDR, did not show any growth inhibition except at extremely high concentrations of 1,25-dihydroxyvitamin D3, namely 10(-5) M. These findings suggest a receptor-mediated mechanism of growth inhibition for 1,25-dihydroxyvitamin D3 and a role for this hormone in the growth of malignant melanoma cells.


Psychological reactance impacts ratings of pediatrician vaccine-related communication quality, perceived vaccine safety, and vaccination priority among U.S. parents.
Physician communication surrounding vaccination is important in driving patient compliance with schedules and recommendations, but patient psychological factors suggest that communication strategies may have differential effects on patients. This paper investigates how psychological reactance, defined as an individuals' propensity to restore their autonomy when they perceive that others are trying to impose their will on them, impacts perceptions about physician communication and perceptions and prioritizations of vaccination. We propose and describe the results of a study that was conducted to assess the relationship between individual differences in reactance, perceived quality of pediatrician communication, perceptions of vaccination safety, and vaccination prioritization using a sample of parents. We recruited 300 parent participants via the online platform Prolific Academic in which they completed a computer-mediated survey. Results show that compared to those who are low in psychological reactance, those high in psychological reactance place less of a priority on vaccination, and that this relationship is driven by evaluations of physician communication quality and perceived vaccine safety. Our findings suggest that physicians should not adopt a one-size-fits-all approach when interacting with patients and should tailor messaging to patients based on psychological factors including reactance.


The ecto-enzyme CD38 is a nicotinic acid adenine dinucleotide phosphate (NAADP) synthase that couples receptor activation to Ca2+ mobilization from lysosomes in pancreatic acinar cells.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-mobilizing intracellular messenger and is linked to a variety of stimuli and cell surface receptors. However, the enzyme responsible for endogenous NAADP synthesis in vivo is unknown, and it has been proposed that another enzyme differing from ADP-ribosyl cyclase family members may exist. The ecto-enzyme CD38, involved in many functions as diverse as cell proliferation and social behavior, represents an important alternative. In pancreatic acinar cells, the hormone cholecystokinin (CCK) stimulates NAADP production evoking Ca(2+) signals by discharging acidic Ca(2+) stores and leading to digestive enzyme secretion. From cells derived from CD38(-/-) mice, we provide the first physiological evidence that CD38 is required for endogenous NAADP generation in response to CCK stimulation. Furthermore, CD38 expression in CD38-deficient pancreatic AR42J cells remodels Ca(2+)-signaling pathways in these cells by restoring Ca(2+) mobilization from lysosomes during CCK-induced Ca(2+) signaling. In agreement with an intracellular site for messenger synthesis, we found that CD38 is expressed in endosomes. These CD38-containing vesicles, likely of endosomal origin, appear to be proximal to lysosomes but not co-localized with them. We propose that CD38 is an NAADP synthase required for coupling receptor activation to NAADP-mediated Ca(2+) release from lysosomal stores in pancreatic acinar cells.


SNP discovery from transcriptome of the swimbladder of Takifugu rubripes.
Single nucleotide polymorphisms (SNPs) have become the marker of choice for genome-wide association studies in many species. High-throughput sequencing of RNA was developed primarily to analyze global gene expression, while it is an efficient way to discover SNPs from the expressed genes. In this study, we conducted transcriptome sequencing of the swimbladder of Takifugu rubripes using Illumina HiSeq2000 platform to identify gene-associated SNPs in the swimbladder. A total of 30,312,181 unique-mapped-reads were obtained from 44,736,850 raw reads. A total of 62,270 putative SNPs were discovered, which were located in 11,306 expressed genes and 2,246 scaffolds. The average minor allele frequency (MAF) of the SNPs was 0.26. GO and KEGG pathway analysis were conducted to analyze the genes containing SNPs. Validation of selected SNPs revealed that 54% of SNPs (26/48) were true SNPs. The results suggest that RNA-Seq is an efficient and cost-effective approach to discover gene-associated SNPs. In this study, a large number of SNPs were identified and these data will be useful resources for population genetic study, evolution analysis, resource assessment, genetic linkage analysis and genome-wide association studies.


A deficit in face-voice integration in developing vervet monkeys exposed to ethanol during gestation.
Children with fetal alcohol spectrum disorders display behavioural and intellectual impairments that strongly implicate dysfunction within the frontal cortex. Deficits in social behaviour and cognition are amongst the most pervasive outcomes of prenatal ethanol exposure. Our naturalistic vervet monkey model of fetal alcohol exposure (FAE) provides an unparalleled opportunity to study the neurobehavioral outcomes of prenatal ethanol exposure in a controlled experimental setting. Recent work has revealed a significant reduction of the neuronal population in the frontal lobes of these monkeys. We used an intersensory matching procedure to investigate audiovisual perception of socially relevant stimuli in young FAE vervet monkeys. Here we show a domain-specific deficit in audiovisual integration of socially relevant stimuli. When FAE monkeys were shown a pair of side-by-side videos of a monkey concurrently presenting two different calls along with a single audio track matching the content of one of the calls, they were not able to match the correct video to the single audio track. This was manifest by their average looking time being equally spent towards both the matching and non-matching videos. However, a group of normally developing monkeys exhibited a significant preference for the non-matching video. This inability to integrate and thereby discriminate audiovisual stimuli was confined to the integration of faces and voices as revealed by the monkeys' ability to match a dynamic face to a complex tone or a black-and-white checkerboard to a pure tone, presumably based on duration and/or onset-offset synchrony. Together, these results suggest that prenatal ethanol exposure negatively affects a specific domain of audiovisual integration. This deficit is confined to the integration of information that is presented by the face and the voice and does not affect more elementary aspects of sensory integration.


Interior point algorithms: guaranteed optimality for fluence map optimization in IMRT.
One of the most widely studied problems of the intensity-modulated radiation therapy (IMRT) treatment planning problem is the fluence map optimization (FMO) problem, the problem of determining the amount of radiation intensity, or fluence, of each beamlet in each beam. For a given set of beams, the fluences of the beamlets can drastically affect the quality of the treatment plan, and thus it is critical to obtain good fluence maps for radiation delivery. Although several approaches have been shown to yield good solutions to the FMO problem, these solutions are not guaranteed to be optimal. This shortcoming can be attributed to either optimization model complexity or properties of the algorithms used to solve the optimization model. We present a convex FMO formulation and an interior point algorithm that yields an optimal treatment plan in seconds, making it a viable option for clinical applications.


Prospective study of the disadvantage of people from ethnic minority groups applying to medical schools in the United Kingdom.
To assess whether the ethnic origin of applicants affects their likelihood of being accepted into medical school in the United Kingdom the outcome for the 2399 applicants who applied to read medicine at university in 1986 and included St Mary's Hospital Medical School as one of their five choices was studied prospectively. Altogether 2040 of the 2399 applicants were British (United Kingdom) nationals, constituting 24.7% (n = 8249) of all home applicants for medicine in 1986, and 1971 of them with postal addresses in the United Kingdom were sent questionnaires asking about their ethnic origin, whether English was their first language, and about their attitudes to ethnic monitoring. A total of 1817 (92.2%) applicants returned the questionnaire, 401 (22.6%) saying that they were from an ethnic minority group and 393 (21.6%) having non-European surnames. Multiple logistic regression identified 11 significant predictors of successful application, of which grades at O and A level, application after A levels, and date of application were the most important. After taking these four variables into account the predicted acceptance rates for home students on the basis of their application forms alone were 47.8% for white applicants and 35.6% for applicants from ethnic minority groups compared with actual acceptance rates of 49.6% and 27.3%, respectively. The difference in success of white and non-white applicants could partly but not entirely be explained by differences in the characteristics considered to be important in a professional context by selectors during shortlisting of candidates: academic ability, interests, and contribution to the community. No differences in the success rate of applicants from ethnic minority groups to individual medical schools could be identified. More research is needed to discover how perceptions of professional suitability are assessed from application forms and interviews.


Fluorescence nanoscopy in cell biology.
Fluorescence nanoscopy uniquely combines minimally invasive optical access to the internal nanoscale structure and dynamics of cells and tissues with molecular detection specificity. While the basic physical principles of 'super-resolution' imaging were discovered in the 1990s, with initial experimental demonstrations following in 2000, the broad application of super-resolution imaging to address cell-biological questions has only more recently emerged. Nanoscopy approaches have begun to facilitate discoveries in cell biology and to add new knowledge. One current direction for method improvement is the ambition to quantitatively account for each molecule under investigation and assess true molecular colocalization patterns via multi-colour analyses. In pursuing this goal, the labelling of individual molecules to enable their visualization has emerged as a central challenge. Extending nanoscale imaging into (sliced) tissue and whole-animal contexts is a further goal. In this Review we describe the successes to date and discuss current obstacles and possibilities for further development.


Detection, quantification, and total synthesis of novel 3-hydroxykynurenine glucoside-derived metabolites present in human lenses.
3-Hydroxykynurenine O-β-D-glucoside (3OHKG) protects the lens from UV damage, and novel related species may act analogously. The aim of this study was to detect, quantify, and elucidate the structures of novel 3-hydroxykynurenine glucoside-derived metabolites present in the human lens. Compounds were detected and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 24 human lenses of different ages, of which 22 were normal and two had cataract. Structures of these were confirmed through total synthesis. 3OHKG concentrations decreased with age in the lens nuclei, whereas the levels of three novel species, 4-(2-amino-3-hydroxyphenyl)-2-hydroxy-4-oxobutanoic acid O-β-D-glucoside (3OHKG-W), 3-hydroxykynurenine O-β-D-glucoside yellow (3OHKG-Y), and 2-amino-3-hydroxyacetophenone O-β-D-glucoside (AHAG), increased, though to different extents. In contrast, the concentrations present in the cortex of the lens remained constant with age. Three novel 3OHKG-derived metabolites have been detected in extracts from human lenses.


Comparing the substrate specificities of cytochrome c biogenesis Systems I and II: bioenergetics.
c-Type cytochromes require specific post-translational protein systems, which vary in different organisms, for the characteristic covalent attachment of heme to the cytochrome polypeptide. Cytochrome c biogenesis System II, found in chloroplasts and many bacteria, comprises four subunits, two of which (ResB and ResC) are the minimal functional unit. The ycf5 gene from Helicobacter pylori encodes a fusion of ResB and ResC. Heterologous expression of ResBC in Escherichia coli lacking its own biogenesis machinery allowed us to investigate the substrate specificity of System II. ResBC is able to attach heme to monoheme c-type cytochromes c(550) from Paracoccus denitrificans and c(552) from Hydrogenobacter thermophilus, both normally matured by System I. The production of holocytochrome is enhanced by the addition of exogenous reductant. Single-cysteine variants of these cytochromes were not efficiently matured by System II, but System I was able to produce detectable amounts of AXXCH variants; this adds to evidence that there is no obligate requirement for a disulfide-bonded intermediate for the latter c-type cytochrome biogenesis system. In addition, System II was able to mature an AXXAH-containing variant into a b-type cytochrome, with implications for both heme supply to the periplasm and substrate recognition by System II.


Genetic pathways in colorectal and other cancers.
Cells from cancers show aberrant behaviour such as unrestrained growth, invasion into adjacent tissue and metastasis. All these features of cancer cell behaviour can be explained in terms of genetic changes and the functional impact of these changes. In this review, colorectal cancer (CRC) is examined as a classical example of multistep carcinogenesis. First there is an overview which shows that cancers develop by a process of somatic evolution. This gives rise to preferred genetic pathways of tumorigenesis. The factors which may influence the development and ultimate choice of genetic pathways are then examined. Next, CRC is studied as a specific disease and the putative genetic pathways are described. The mutations that comprise these pathways and the possible functional sequelae of these are explored. The review concludes with a look at those avenues which may further elucidate the natural history of CRC and lead to improved therapy.


IgG2a restriction of murine antibodies elicited by viral infections.
The isotypic distribution of IgG antibodies was determined in the serum of mice after infection with a panel of RNA and DNA viruses representative of 11 different genera. The antiviral response induced by all these viruses showed a striking preponderance of the IgG2a subclass whatever the strain of mice tested or the time elapsed after infection. Together with the predominance of IgG1 in antiprotein and of IgG3 in anticarbohydrate response, this IgG2a restriction of antiviral antibodies strongly suggests the existence of highly specific mechanisms for the regulation of individual subclasses in the mouse.


Prospective nationwide surveillance of hospitalizations due to pertussis in children, 2006-2010.
Frequency of pertussis is highly variable from country to country and it depends on multiple factors including case definitions and type of surveillance systems used. Many countries recently reported an increase of pertussis cases especially in infants and adolescents. From April 2006 to March 2011, 15-year-old patients hospitalized with suspected or proven pertussis were reported to the Swiss Pediatric Surveillance Unit. Patients with ≥14 days of cough plus paroxysms, whooping or post-tussive vomiting fulfilled the clinical case definition of pertussis. For laboratory confirmation, Bordetella pertussis polymerase chain reaction was offered free of charge. Data were available from 159 of 173 reported cases and 130 (90% of them <12 months old) were eligible including 125 laboratory-confirmed B. pertussis infections. Rates per 100,000 population were 2.6 (<16 years) and 38.8 (<12 months), respectively. Most frequent complications were cyanosis (63%) and sleep disturbance (60%); 35 (27%) patients received intensive care and 1 patient died. Source of infection was known in 79 (61%) patients and was mainly a sibling, parent or both. Most patients were unimmunized (65%) or incompletely immunized (30%). The high rate of pertussis hospitalization in young infants established in this surveillance project and the incomplete pertussis immunization status in almost all hospitalized patients require further efforts for improvement. In addition, introduction of pertussis immunizations for all adolescents (in 2013), young adults (in 2012) and pregnant women (in 2013) in Switzerland should increase indirect protection of vulnerable newborns and infants too young to be fully immunized.


[Acute kidney injury in severe sepsis].
Sepsis affects 40% of critically ill patients, with a reported mortality of approximately 30% in severe sepsis, raising to 75% when acute kidney injury ensues, which occurs in about 20-51% of cases. The present study consists on a one-year prospective, observational, longitudinal trial undergone in 80 severe septic patients to determine the risk of development of acute kidney injury and its relationship with mortality; the association of the clinical course and blood parameter variations with mortality; the severe sepsis mortality rate; an eventual correlation between death and septic focus, and to assess mortality predictibility based on initial creatinine levels and final variations. Two groups were defined: Dead (n=25) and Not-dead (n=55). According to creatinine on admission, 39 subjects presented with normal creatinine levels (10 deaths) and 41 presented elevated creatinine measurements (15 deaths); regarding final creatinine levels, 48 presented normal levels and 7 patients died, while 32 developed acute kidney injury, with 18 deaths. Of the total of 25 deaths, 72% presented renal injury. Seven alive patients and 2 deceased patients required hemodialysis. The most frequent primary septic focus was the airway (26.4%). The development of kidney injury is a high predictor of mortality in sepsis, independent of initial serum creatinine levels. Older patients, hypertension, a higher APACHE score, a more severe degree of anemia, hypoalbuminemia, hyperphosphatemia and hyperkalemia were associated with a higher mortality rate. The global mortality was: 31.3%. The failure to identify the primary septic focus was associated with higher mortality. The respiratory focus was related with a higher risk to require hemodialysis.


Building capacity for water, sanitation, and hygiene programming: Training evaluation theory applied to CLTS management training in Kenya.
Training and capacity building are long established critical components of global water, sanitation, and hygiene (WaSH) policies, strategies, and programs. Expanding capacity building support for WaSH in developing countries is one of the targets of the Sustainable Development Goals. There are many training evaluation methods and tools available. However, training evaluations in WaSH have been infrequent, have often not utilized these methods and tools, and have lacked rigor. We developed a conceptual framework for evaluating training in WaSH by reviewing and adapting concepts from literature. Our framework includes three target outcomes: learning, individual performance, and improved programming; and two sets of influences: trainee and context factors. We applied the framework to evaluate a seven-month community-led total sanitation (CLTS) management training program delivered to 42 government officials in Kenya from September 2013 to May 2014. Trainees were given a pre-training questionnaire and were interviewed at two weeks and seven months after initial training. We qualitatively analyzed the data using our conceptual framework. The training program resulted in trainees learning the CLTS process and new skills, and improving their individual performance through application of advocacy, partnership, and supervision soft skills. The link from trainees' performance to improved programming was constrained by resource limitations and pre-existing rigidity of trainees' organizations. Training-over-time enhanced outcomes and enabled trainees to overcome constraints in their work. Training in soft skills is relevant to managing public health programs beyond WaSH. We make recommendations on how training programs can be targeted and adapted to improve outcomes. Our conceptual framework can be used as a tool both for planning and evaluating training programs in WaSH.


Patterns of inpatient care for immigrants in Switzerland: a case control study.
Migration has become a major political and social concern in West European societies. A case-control method was used to analyse the utilisation of inpatient mental health services by immigrants from a catchment area in Switzerland over a 7-year period. Compared to natives, immigrants had fewer psychiatric hospitalisations, but more emergency and compulsory admissions. During inpatient treatment, they received less psycho-, ergo- and physiotherapy. Other therapies as well as compulsory measures were at comparable rates, as was the frequency of irregular discharge. They spent shorter periods as inpatients and the rate of psychiatric readmissions was significantly lower. Comparison of different countries of origin revealed that only patients from West and North Europe were comparable to natives regarding type of referral, inpatient treatment, and longitudinal measures of service utilisation. Even after accounting for effects of social class, immigrants from South Europe, former Yugoslavia, Turkey, East Europe and more distant countries spent significantly shorter time in inpatient treatment, compared to Swiss control patients. Results of this study clearly point to an underutilisation of inpatient facilities among immigrants with mental disorders, and to disadvantages in psychiatric inpatient care. This, however, does not pertain to all foreign patients to the same extent: inequalities of mental health service use are particularly pronounced in immigrants from more distant countries.


Insomnia and hypertension: A systematic review.
Insomnia is a prevalent sleep disorder that is associated with a multitude of health consequences. Particularly, insomnia has been associated with cardiovascular disease and its precursors, such as hypertension and blood pressure (BP) non-dipping. The present systematic review aimed to summarize the evidence on the concurrent and prospective associations between insomnia and hypertension and/or BP. Using electronic search engines (PubMed, SCOPUS, PsycINFO), 5,618 articles published from January 1970 to December 2017 were identified, and 64 met the inclusion criteria (26 to 162,121 participants; age range: 18-100; 46.4% male). Insomnia was based on diagnostic or non-diagnostic criteria. Hypertension was based on self-or physician-reports, antihypertensive medication use, and/or measured BP. Findings indicate that when insomnia is frequent, chronic, and/or accompanied with short sleep duration or objective markers of arousal, there is a strong association with hypertension/BP. Based on limited studies, hypertension did not significantly predict future insomnia in middle-aged adults, but did in older adults. Based on a majority of case-control studies, no differences in BP were found between participants with and without insomnia. Further research is needed to identify putative pathophysiological mechanisms underlying the link between insomnia and hypertension. The impact of insomnia therapy on BP should also be further examined in the future.


Pain, objectivity and history: understanding pain stigma.
The primary claim of this paper is that understanding the stigma so commonly endured by chronic pain sufferers today in the USA and the UK is unlikely without proper appreciation of the history of pain. Ameliorating such stigma is an ethical imperative, and yet most approaches eschew even an attempt to trace connections between historical attitudes, practices and beliefs towards pain and the stigmatisation so many pain sufferers currently endure. The manuscript aims to help fill this gap by framing pain in the modern era in context of two crucial intellectual schemes that waxed in the 19th and 20th centuries: mechanical objectivity and somaticism. The analysis explains these frameworks and applies them to exploration of primary sources connected to contested pain conditions such as railway spine. By properly situating the historical roots of what it means to cite the 'subjectivity' of pain as a problem, the modern roots of stigmatising attitudes and practices towards chronic pain sufferers become much clearer. The manuscript concludes by suggesting that interventions expressly intended to target the root causes of such stigma are much more likely to be successful than approaches that proceed in ignorance of the historical forces shaping and driving pain stigma in the present.


Leishmania dual-specificity tyrosine-regulated kinase 1 (DYRK1) is required for sustaining Leishmania stationary phase phenotype.
Although the multiplicative and growth-arrested states play key roles in Leishmania development, the regulators of these transitions are largely unknown. In an attempt to gain a better understanding of these processes, we characterised one member of a family of protein kinases with dual specificity, LinDYRK1, which acts as a stasis regulator in other organisms. LinDYRK1 overexpressing parasites displayed a decrease in proliferation and in cell cycle re-entry of arrested cells. Parasites lacking LinDYRK1 displayed distinct fitness phenotypes in logarithmic and stationary growth phases. In logarithmic growth phase, LinDYRK1-/- parasites proliferated better than control lines, supporting a role of this kinase in stasis, while in stationary growth phase, LinDYRK1-/- parasites had important defects as they rounded up, accumulated vacuoles and lipid bodies and displayed subtle but consistent differences in lipid composition. Moreover, they expressed less metacyclic-enriched transcripts, displayed increased sensitivity to complement lysis and a significant reduction in survival within peritoneal macrophages. The distinct LinDYRK1-/- growth phase phenotypes were mirrored by the distinct LinDYRK1 localisations in logarithmic (mainly in flagellar pocket area and endosomes) and late stationary phase (mitochondrion). Overall, this work provides first evidence for the role of a DYRK family member in sustaining promastigote stationary phase phenotype and infectivity.


Ultrasensitive monitoring of HIV-1 viral load by a low-cost real-time reverse transcription-PCR assay with internal control for the 5' long terminal repeat domain.
Current HIV-1 viral-load assays are too expensive for resource-limited settings. In some countries, monitoring of antiretroviral therapy is now more expensive than treatment itself. In addition, some commercial assays have shown shortcomings in quantifying rare genotypes. We evaluated real-time reverse transcription-PCR with internal control targeting the conserved long terminal repeat (LTR) domain of HIV-1 on reference panels and patient samples from Brazil (n = 1186), South Africa (n = 130), India (n = 44), and Germany (n = 127). The detection limit was 31.9 IU of HIV-1 RNA/mL of plasma (> 95% probability of detection, Probit analysis). The internal control showed inhibition in 3.7% of samples (95% confidence interval, 2.32%-5.9%; n = 454; 40 different runs). Comparative qualitative testing yielded the following: Roche Amplicor vs LTR assay (n = 431 samples), 51.7% vs 65% positives; Amplicor Ultrasensitive vs LTR (n = 133), 81.2% vs 82.7%; BioMerieux NucliSens HIV-1 QT (n = 453), 60.5% vs 65.1%; Bayer Versant 3.0 (n = 433), 57.7% vs 55.4%; total (n = 1450), 59.0% vs 63.8% positives. Intra-/interassay variability at medium and near-negative concentrations was 18%-51%. The quantification range was 50-10,000,000 IU/mL. Viral loads for subtypes A-D, F-J, AE, and AG yielded mean differences of 0.31 log(10) compared with Amplicor in the 10(3)-10(4) IU/mL range. HIV-1 N and O were not detected by Amplicor, but yielded up to 180 180.00 IU/mL in the LTR assay. Viral loads in stored samples from all countries, compared with Amplicor, NucliSens, or Versant, yielded regression line slopes (SD) of 0.9 (0.13) (P < 0.001 for all). This method offers all features of commercial assays and covers all relevant genotypes. It could allow general monitoring of antiretroviral therapy in resource-limited settings.


Emulsion-Based RIR-MAPLE Deposition of Conjugated Polymers: Primary Solvent Effect and Its Implications on Organic Solar Cell Performance.
Emulsion-based, resonant infrared matrix-assisted pulsed laser evaporation (RIR-MAPLE) has been demonstrated as an alternative technique to deposit conjugated polymer films for photovoltaic applications; yet, a fundamental understanding of how the emulsion target characteristics translate into film properties and solar cell performance is unclear. Such understanding is crucial to enable the rational improvement of organic solar cell (OSC) efficiency and to realize the expected advantages of emulsion-based RIR-MAPLE for OSC fabrication. In this paper, the effect of the primary solvent used in the emulsion target is studied, both experimentally and theoretically, and it is found to determine the conjugated polymer cluster size in the emulsion as well as surface roughness and internal morphology of resulting polymer films. By using a primary solvent with low solubility-in-water and low vapor pressure, the surface roughness of deposited P3HT and PCPDTBT polymer films was reduced to 10 nm, and the efficiency of P3HT:PC61BM OSCs was increased to 3.2% (∼100 times higher compared to the first MAPLE OSC demonstration [ Caricato , A. P. ; Appl. Phys. Lett. 2012 , 100 , 073306 ]). This work unveils the mechanism of polymer film formation using emulsion-based RIR-MAPLE and provides insight and direction to determine the best ways to take advantage of the emulsion target approach to control film properties for different applications.


The dynamics of social-ecological systems in urban landscapes: Stockholm and the National Urban Park, Sweden.
This study addresses social-ecological dynamics in the greater metropolitan area of Stockholm County, Sweden, with special focus on the National Urban Park (NUP). It is part of the Millennium Ecosystem Assessment (MA) and has the following specific objectives: (1) to provide scientific information on biodiversity patterns, ecosystem dynamics, and ecosystem services generated; (2) to map interplay between actors and institutions involved in management of ecosystem services; and (3) to identify strategies for strengthening social-ecological resilience. The green areas in Stockholm County deliver numerous ecosystem services, for example, air filtration, regulation of microclimate, noise reduction, surface water drainage, recreational and cultural values, nutrient retention, and pollination and seed dispersal. Recreation is among the most important services and NUP, for example, has more than 15 million visitors per year. More than 65 organizations representing 175,000 members are involved in management of ecosystem services. However, because of population increase and urban growth during the last three decades, the region displays a quite dramatic loss of green areas and biodiversity. An important future focus is how management may reduce increasing isolation of urban green areas and enhance connectivity. Comanagement should be considered where locally managed green space may function as buffer zones and for management of weak links that connect larger green areas; for example, there are three such areas around NUP identified. Preliminary results indicate that areas of informal management represent centers on which to base adaptive comanagement, with the potential to strengthen biodiversity management and resilience in the landscape.


New gold pincer-type complexes: synthesis, characterization, DNA binding studies and cytotoxicity.
With the aim of assessing whether Au(iii) compounds with pincer type ligands might be utilized as potential antitumor agents, three new monofunctional Au(iii) complexes of the general formula [Au(N-N'-N)Cl]Cl2, where N-N'-N = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine (H2LtBu, 1), 2,6-bis(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)pyridine (Me2LtBu, 2) or 2,6-bis((4S,7R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine (Me2*L, 3) were synthesized. All complexes were characterized by elemental analysis, spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR) and mass spectrometry (MALDI TOF MS). The chemical behavior of the complexes under physiological conditions was studied by UV-Vis spectroscopy, which showed that all compounds were remarkably stable and that the gold center remained in the 3+ oxidation state. The kinetics and the mechanism of the reaction of complexes 1-3 with guanine derivatives (i.e. guanosine (Guo) and guanosine-5'-monophosphate (5'-GMP)) and calf thymus DNA (CT DNA) were studied by stopped-flow spectroscopy. The three complexes displayed moderately different rate constants in their reactions with Guo, 5'-GMP and CT DNA, which can be explained by the steric hindrance and σ-donicity of the methyl substituent on the bis-pyrazolylpyridine fragment in complexes 2 and 3. The measured enthalpies and entropies of activation (ΔH≠ > 0, ΔS≠ < 0) supported an associative mechanism for the substitution process. The interaction of the newly synthesized complexes 1-3 with CT DNA was investigated by UV-Vis and fluorescence spectroscopy, and also by viscosity measurements, which all indicated that complexes 1-3 bound to CT DNA with moderate binding affinity (Kb = 1.6-5.7 × 103 M-1) and stabilized the duplex of CT DNA. Molecular docking indicated that complexes 1-3 interacted with DNA via intercalation. Complex 1 reduced the cell survival of all the investigated cell lines (A549, A375, and LS-174) with IC50 values being up to 20 μM. We have shown that 1 induced perturbations of the cell cycle and led to apoptosis in human melanoma A375 cells. Complex 1 also affected the level of reactive oxygen species (ROS) in the same cells. However, pre-treatment of A375 cells with NAC (ROS scavenger) reversed the effect of 1 on their survival.


A computerized reminder system to increase the use of preventive care for hospitalized patients.
Although they are effective in outpatient settings, computerized reminders have not been proved to increase preventive care in inpatient settings. We conducted a randomized, controlled trial to determine the effects of computerized reminders on the rates at which four preventive therapies were ordered for inpatients. During an 18-month study period, a computerized system processed on-line information for all 6371 patients admitted to a general-medicine service (for a total of 10,065 hospitalizations), generating preventive care reminders as appropriate. Physicians who were in the intervention group viewed these reminders when they were using a computerized order-entry system for inpatients. The reminder system identified 3416 patients (53.6 percent) as eligible for preventive measures that had not been ordered by the admitting physician. For patients with at least one indication, computerized reminders resulted in higher adjusted ordering rates for pneumococcal vaccination (35.8 percent of the patients in the intervention group vs. 0.8 percent of those in the control group, P<0.001), influenza vaccination (51.4 percent vs. 1.0 percent, P< 0.001), prophylactic heparin (32.2 percent vs. 18.9 percent, P<0.001), and prophylactic aspirin at discharge (36.4 percent vs. 27.6 percent, P<0.001). A majority of hospitalized patients in this study were eligible for preventive measures, and computerized reminders significantly increased the rate of delivery of such therapies.


Expression of conditioned preference for low-quality food in sheep is modulated by foraging costs.
Past positive experiences can increase herbivores' motivation to eat low-quality foods. However, this is not always translated into a higher preference for low-quality foods in choice tests among foods of higher nutritional quality. Foraging behavior is also affected by properties of the feeding context because the quality and abundance of foods in nature change in time and space. We hypothesized that in a choice situation, the expression of a past positive experience with a low-quality food is modulated by the costs associated with selecting a high-quality food option. A total of 24 sheep were randomly assigned into two groups (n=12). During conditioning phase, one group (CS+; i.e., conditioned group) was fed with oat hay (a low-quality food) for 20 min and immediately after a ration of soybean meal (a nutritious food), whereas the other group was also fed with oat hay but the offer of soybean meal was delayed 5 h (CS-; i.e., control group). After conditioning, we assessed sheep motivation to eat the oat hay in an experimental arena in which accessibility to alfalfa hay (a high-quality food) was increasingly restricted. When alfalfa hay was readily accessible, CS+ and CS- sheep almost exclusively selected this food, showing a small and similar preference for oat hay. However, when accessibility to alfalfa hay decreased, intake and selection of oat hay was greater in the CS+ sheep than in the CS- sheep. The latter was a consequence of differential changes in behavior between groups; for example, sheep in CS+ spent more time foraging oat hay and were more likely to switch to oat hay if they had previously been eating alfalfa hay than sheep in CS-. Our results show that behavioral expression of the conditioned preference for a low-quality food depends on parameters of the feeding context (e.g., availability). We suggest that this can be the link between learning models and optimal foraging models of diet selection.


Evaluation of Chlamydia Partner Notification Practices and Use of the "Let Them Know" Website by Family Planning Clinicians in Australia: Cross-Sectional Study.
Chlamydia, caused by Chlamydia trachomatis, is the most common reportable infection in many developed countries. Testing, treatment, and partner notification (PN) are key strategies for chlamydia control. In 2008 the Let Them Know (LTK) PN website was established, which provided means for people to send anonymous PN messages by text messaging (short message service, SMS), email, or letter. We evaluated PN practices among Australian family planning clinicians following chlamydia diagnosis and assessed how often clinicians refer their patients to the LTK website. A mixed methods approach included a Web-based cross-sectional survey of Australian family planning clinicians to examine PN attitudes and practices and focus groups to explore the context of LTK website use. Between May 2012 and June 2012, all clinicians from 29 different family planning services (n=212) were invited to complete the survey, and 164 participated (response rate=77.4%); of the clinicians, 96.3% (158/164) were females, 56.1% (92/164) nurses, and 43.9% (72/164) doctors. More than half (62.2%, 92/148) agreed that PN was primarily the client's responsibility; however, 93.2% (138/148) agreed it was the clinician's responsibility to support the client in informing their partners by providing information or access to resources. Almost half (49.4%, 76/154) of the clinicians said that they always or usually referred clients to the LTK website, with variation across clinics in Australian states and territories (0%-77%). Eleven focus groups among 70 clinicians at 11 family planning services found that the LTK website had been integrated into routine practice; that it was particularly useful for clients who found it difficult to contact partners; and that the LTK letters and fact sheets were useful. However, many clinicians were not aware of the website and noted a lack of internal clinic training about LTK. The LTK website has become an important PN tool for family planning clinicians. The variation in referral of patients to the LTK website and lack of awareness among some clinicians suggest further promotion of the website, PN training, and clinic protocols are warranted.


Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 - 2018.
São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species.


Purification and biochemical characterization of the ATP synthase from Heliobacterium modesticaldum.
Heliobacterium modesticaldum is an anaerobic photosynthetic bacterium that grows optimally at pH 6-7 and 52°C and is the only phototrophic member of the Firmicutes phylum family (gram-positive bacteria with low GC content). The ATP synthase of H. modesticaldum was isolated and characterized at the biochemical and biophysical levels. The isolated holoenzyme exhibited the subunit patterns of F-type ATP synthases containing a 5-subunit hydrophilic F1 subcomplex and a 3-subunit hydrophobic F0 subcomplex. ATP hydrolysis by the isolated HF1F0 ATP synthase was successfully detected after pretreatment with different detergents by an in-gel ATPase activity assay, which showed that the highest activity was detected in the presence of mild detergents such as LDAO; moreover, high catalytic activity in the gel was already detected after the initial incubation period of 0.5h. In contrast, HF1F0 showed extremely low ATPase activity in harsher detergents such as TODC. The isolated fully functional enzyme will form the basis for future structural studies.


Virtual patients: an effective educational intervention to improve paediatric basic specialist trainee education in the management of suspected child abuse?
Child abuse is a particularly difficult subject to teach at both undergraduate and postgraduate level. Most doctors are dissatisfied with their training in child abuse recognition and management. We developed an interactive video based Virtual Patient to provide formal training for paediatric Basic Specialist Trainees in the recognition of suspected child abuse. The Virtual Patient case revolves around the management of suspected physical abuse in a seven month old child, who initially presents to the Emergency Department with viral upper respiratory tract symptoms. This Virtual Patient was used to facilitate a case discussion with Basic Specialist Trainees. A questionnaire was developed to determine their perception of the value of the Virtual Patient as an educational tool. Twenty five Basic Specialist Trainees completed the questionnaire. Upon completion of the case, 23/25 (92%) participants reported greater self confidence in their ability to recognize cases of suspected child abuse and 24/25 (96%) of participants reported greater self confidence in their ability to report cases of suspected child abuse. Basic Specialist Trainees perceived the Virtual Patient to be a useful educational tool. Virtual Patients may have a role to play in enhancing postgraduate training in the recognition of suspected child abuse.


[Microbiología, sensibilidad antibiótica y factores asociados a bacteriemia en la prostatitis aguda].
The aim of the study was to analyze the characteristics of patients with acute prostatitis presenting to the Emergency Department, the microbiological findings, antibiotic susceptibility, and bacteraemia associated factors. Observational and cohort study with prospective follow-up including patients with acute prostatitis presenting to the Emergency Department from January-December 2012. Data were collected for demographic variables, comorbidities, microbiological findings, antibiotic treatment and outcome. Two hundred and forty one episodes of acute prostatitis were included. Mean age was 62.9 ± 16 years, a history of prostate adenoma was reported in 54 cases (22.5%) and prior manipulation of the lower urinary tract in 40 (17%). Mean symptoms duration was 3.38 ± 4.04 days, voiding symptoms were present in 176 cases (73%) and fever in 154 (64%). Seventy patients (29%) were admitted to the hospital and 3 died. From 216 urine cultures, 128 were positive (59%) and 24 (17.6%) out of 136 blood cultures. Escherichia coli was the main pathogen (58.6% of urine cultures and 64% of blood cultures) with resistant strains to fluoroquinolones, cotrimoxazole and amoxicillin/clavulanic in 27.7%, 22.9% and 27.7% of cases respectively. In the univariate analysis, only chills were associated to bacteraemia (p=0.013). At 30-day follow-up, patients with bacteraemia returned more frequently to the Emergency Department (p=0.037) and were more often admitted to the hospital (p=0.003). Patients with acute prostatitis discharged from the Emergency Department need clinical follow-up and monitoring of microbiological findings in order to assure an adequate antibiotic treatment. Return to Emergency Department and admission to the hospital were significantly more frequent among patients with bacteraemia.


Spontaneously forming ellipsoidal phospholipid unilamellar vesicles and their interactions with helical domains of saposin C.
We have observed a bimodal distribution of ellipsoidal unilamellar vesicles (ULVs) in a phospholipid mixture composed of dioleoyl phosphatidylserine (DOPS) and dipalmitoyl and dihexanoyl phosphatidylcholine, DPPC and DHPC, respectively. Dynamic light scattering and transmission electron microscopy data indicate a bimodal size distribution of these nanoparticles with hydrodynamic radii of approximately 200 and >500 nm, while small-angle neutron scattering data were fit using a model of coexisting monodisperse morphologies, namely, oblate and triaxial ellipsoidal vesicles. Unlike DOPS ULV formed by sonication, which can fuse days after being formed, these ULVs are stable over a period of 12 months at 4 degrees C. We also report on the structure of these ULVs associated with the two helical peptide domains (H1 and H2) of a glucosylprotein, namely, Saposin C, to gain some insight into protein-membrane interactions.


Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau-/- mice.
Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore Aβ-mediated inhibition on a mouse Tau-/- background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human MAPT locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a Tau-/- background. We found that the human wild-type MAPT H1 locus was able to restore Aβ42-mediated impairment of LTP. In contrast, Aβ42 did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human MAPT is able to restore Aβ42-mediated inhibition of LTP in Tau-/- mice. These results provide further evidence that tau protein is central to Aβ-induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.


Can an online clinical data management service help in improving data collection and data quality in a developing country setting?
Data collection by electronic medical record (EMR) systems have been proven to be helpful in data collection for scientific research and in improving healthcare. For a multi-centre trial in Indonesia and the Netherlands a web based system was selected to enable all participating centres to easily access data. This study assesses whether the introduction of a clinical trial data management service (CTDMS) composed of electronic case report forms (eCRF) can result in effective data collection and treatment monitoring. Data items entered were checked for inconsistencies automatically when submitted online. The data were divided into primary and secondary data items. We analysed both the total number of errors and the change in error rate, for both primary and secondary items, over the first five month of the trial. In the first five months 51 patients were entered. The primary data error rate was 1.6%, whilst that for secondary data was 2.7% against acceptable error rates for analysis of 1% and 2.5% respectively. The presented analysis shows that after five months since the introduction of the CTDMS the primary and secondary data error rates reflect acceptable levels of data quality. Furthermore, these error rates were decreasing over time. The digital nature of the CTDMS, as well as the online availability of that data, gives fast and easy insight in adherence to treatment protocols. As such, the CTDMS can serve as a tool to train and educate medical doctors and can improve treatment protocols.


Alkali-metal-mediated manganationII of functionalized arenes and applications of ortho-manganated products in Pd-catalyzed cross-coupling reactions with iodobenzene.
Extending the recently introduced concept of "alkali-metal-mediated manganation" to functionalised arenes, the heteroleptic sodium manganate reagent [(tmeda)Na(tmp)(R)Mn(tmp)] (1; TMEDA=N,N,N',N'-tetramethylethylenediamine, TMP=2,2,6,6-tetramethylpiperidide, R=CH2SiMe3) has been treated with anisole or N,N-diisopropylbenzamide in a 1:1 stoichiometry in hexane. These reactions afforded the crystalline products [(tmeda)Na(tmp)(o-C6H4OMe)Mn(tmp)] (2) and [(tmeda)Na(tmp){o-{C(O)N(iPr)2C6H4}Mn(CH2SiMe3] (3), respectively, as determined from X-ray crystallographic studies. On the basis of these products, it can be surmised that reagent 1 has acted, at least partially and ultimately, as an alkyl base in the first reaction liberating the silane Me4Si, but as an amido base in the second reaction liberating the amine TMPH. Both of these paramagnetic products 2 and 3 have contacted ion-pair structures, the key features of which are six-atom, five-element (NaNMnCCO) and seven-atom, five-element (NaNMnCCCO) rings, respectively. Manganates 2 and 3 were successfully cross-coupled with iodobenzene under [PdCl(2)(dppf)] (dppf=1,1'-bis(diphenylphosphino)ferrocene) catalysis to generate unsymmetrical biaryl compounds in yields of 98.0 and 66.2 %, respectively. Emphasizing the importance of alkali-metal mediation in these manganation reactions, the bisalkyl Mn reagent on its own fails to metalate the said benzamide, but instead produces the monomeric, donor-acceptor complex [Mn(R)2{(iPr)2-NC(Ph)(==O)}2] (5), which has also been crystallographically characterised. During one attempt to repeat the synthesis of 2, the butoxide-contaminated complex [{(tmeda)Na(R)(OBu)(o-C6H4OMe)Mn}2] (6) was obtained. In contrast to 2 and 3, due to reduced steric constraints, this complex adopts a dimeric arrangement in the crystal, the centrepiece of which is a twelve atom (NaOCCMnC)2 ring.


Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in β-Hairpin Peptides.
The bulky dehydroamino acids dehydrovaline (ΔVal) and dehydroethylnorvaline (ΔEnv) can be inserted into the turn regions of β-hairpin peptides without altering their secondary structures. These residues increase proteolytic stability, with ΔVal at the (i + 1) position having the most substantial impact. Additionally, a bulky dehydroamino acid can be paired with a d-amino acid (i.e., d-Pro) to synergistically enhance resistance to proteolysis. A link between proteolytic stability and peptide structure is established by the finding that a stabilized ΔVal-containing β-hairpin is more highly folded than its Asn-containing congener.


Tubular and endothelial chimerism in renal allografts using fluorescence and chromogenic in situ hybridization (FISH, CISH) technology.
The role of endothelial and tubular chimerism in renal allograft adaptation and rejection varies in different studies. We addressed the correlation between different clinico-pathological settings and sex-chromosomal endothelial and/or tubular chimerism in renal allografts. We examined the presence or absence of the X and Y chromosomes by fluorescence and chromogenic in situ hybridization (FISH, CISH) methodology on paraffin embedded kidney biopsies in 16 gender mismatched renal transplants (1 to 12 years post-transplantation). Twelve patients were male, four female. Four groups were selected: (i) Vascular calcineurin inhibitor toxicity without rejection; (ii) T-cell mediated vascular rejection; (iii) antibody mediated rejection; and (iv) C4d-positivity in AB0-incompatible transplants with or without rejection. Twelve non-transplant kidney biopsies (8 female, 4 male) were used as controls. Tubular chimerism was detected more frequently (69%) than endothelial chimerism (12%) in renal transplants. One of 12 control patients had tubular and endothelial chimeric cells (8%). The Y chromosome occurred in 8/12 male recipients (67%) in tubular epithelial cells and in 5/12 male recipients (42%) in endothelial cells. Double X chromosomes were detected in 3/4 female recipients in tubular epithelium. Tubular chimerism occurred more often with endothelial chimerism and capillaritis without correlation with other parameters, such as rejection. Combined Y chromosomal tubular and lymphatic endothelial chimerism correlated with T-cell mediated vascular rejection in two out of three patients (66%). Combined Y chromosomal tubular and peritubular capillary chimerism correlated with antibody mediated C4d+ rejection in one out of two patients (50%). Tubular and/or endothelial chimerism occur frequently in gender mismatched renal allografts and, when combined, this is associated with T-cell mediated rejection.


Variability of sequence surrounding the Xist gene in rodents suggests taxon-specific regulation of X chromosome inactivation.
One of the two X chromosomes in female mammalian cells is subject to inactivation (XCI) initiated by the Xist gene. In this study, we examined in rodents (voles and rat) the conservation of the microsatellite region DXPas34, the Tsix gene (antisense counterpart of Xist), and enhancer Xite that have been shown to flank Xist and regulate XCI in mouse. We have found that mouse regions of the Tsix gene major promoter and minisatellite repeat DXPas34 are conserved among rodents. We have also shown that in voles and rat the region homologous to the mouse Tsix major promoter, initiates antisense to Xist transcription and terminates around the Xist gene start site as is observed with mouse Tsix. A conservation of Tsix expression pattern in voles, rat and mice suggests a crucial role of the antisense transcription in regulation of Xist and XIC in rodents. Most surprisingly, we have found that voles lack the regions homologous to the regulatory element Xite, which is instead replaced with the Slc7a3 gene that is unassociated with the X-inactivation centre in any other eutherians studied. Furthermore, we have not identified any transcription that could have the same functions as murine Xite in voles. Overall, our data show that not all the functional elements surrounding Xist in mice are well conserved even within rodents, thereby suggesting that the regulation of XCI may be at least partially taxon-specific.


Identifying Target Risk Factors Using Population Attributable Risks of Ischemic Stroke by Age and Sex.
Estimating age- and sex-specific population attributable risks (PARs) of major risk factors for stroke may be a useful strategy to identify risk factors for targeting preventive strategies. For this case-control matched study, consecutive patients aged 18-90 years and admitted to nine nationwide hospitals with acute ischemic stroke between December 2008 and June 2010, were enrolled as cases. Controls, individually matched by age and sex, were chosen from the 4th Korean National Health & Nutrition Examination Survey (2008-2010). Based on odds ratios and prevalence, standardized according to the age and sex structure of the Korean population, PARs of major risk factors were estimated according to age (young, ≤ 45; middle-aged, 46-65; and elderly, ≥ 66 years) and sex subgroups. In 4,743 matched case-control sets, smoking (PAR, 45.1%) was the greatest contributing risk factor in young men, followed by hypertension (28.5%). In middle-aged men, the greatest contributing factors were smoking (37.4%), hypertension (22.7%), and diabetes (14.6%), whereas in women the greatest factors were hypertension (22.7%) and stroke history (10.6%). In the elderly, hypertension was the leading factor in men (23.7%) and women (23.4%). Other noticeable factors were stroke history (men, 19.7%; women, 17.3%) and diabetes (men, 12.5%; women, 15.1%). In young women, risk factors with a PAR greater than 10% were not found. Smoking cessation in young people and hypertension and diabetes control in older people may be effective in reducing the burden of stroke on the population. In the elderly, secondary prevention could also be emphasized.


Kinematic differences between front crawl sprint and distance swimmers at a distance pace.
The purpose of the study was to determine whether there are differences in kinematics between sprint and distance front crawl specialists when swimming at a distance pace using a six beat kick. Seven sprint and eight distance male specialists performed one maximum 400 m swim through a 6.75 m³ calibrated space recorded by six gen-locked cameras. The following variables were calculated: average swim velocity, stroke length, stroke frequency, upper limb and foot displacement, elbow angle, the shoulder and hip roll angle, duration of the stroke phases and time corresponding to particular events within the stroke cycle relative to hand entry. Differences between the groups were assessed by an independent t-test and effect size (d) calculations for each variable. The groups only differed significantly with respect to the average swim velocity, with the distance swimmers maintaining a greater velocity throughout the 400 m. However, effect sizes were moderate for elbow angle range during the pull phase (d = 0.78) and the total hip roll magnitude (d = 0.76). There was little evidence to suggest that sprint and distance swimmers using a six beat kick pattern differ in technique when swimming at a distance pace and therefore coaches should not encourage the development of different techniques between these groups.


Noncovalent interactions within a synthetic receptor can reinforce guest binding.
Structural and thermodynamic data are presented on the binding properties of anion receptors containing two covalently linked cyclopeptide subunits that bind sulfate and iodide anions with micromolar affinity in aqueous solution. A synchrotron X-ray crystal structure of the sulfate complex of one receptor revealed that the anion is bound between the peptide rings of the biscyclopeptide. Intimate intramolecular contacts between the nonpolar surfaces of the proline rings of the individual receptor moieties in the complex suggest that hydrophobic interactions within the receptor that do not directly involve the guest contribute to complex stability. This finding is supported by a microcalorimetric analysis of the solvent dependence of complex stability, which showed that increasing the water content of the solvent has only a weak influence on the Gibbs energy of binding. Hence, the increasing amount of energy required for desolvating the binding partners in solutions containing more water is almost compensated by the increasingly favorable hydrophobic interactions. Further observations that suggest that guest-induced intra-receptor interactions contribute to guest binding are (i) anion binding of a monomeric cyclopeptide lacking the covalent linkage between the two rings leads to the formation of 2:1 complexes; (ii) in the crystal structure of the 2:1 iodide complex of this monotopic receptor, a similar arrangement of the two cyclopeptide rings has been found as in the sulfate complex of the biscyclopeptide; (iii) complex formation of the monomeric cyclopeptide in aqueous solution is highly cooperative with a large stability constant corresponding to the formation of the 2:1 complexes from relatively instable 1:1 complexes; (iv) the monomeric cyclopeptide forms only 1:1 anion complexes in DMSO where hydrophobic interactions do not take place; and (v) introducing polar hydroxy groups on the proline rings of the monomeric cyclopeptide disrupts cooperativity causing the formation of only 1:1 complexes even in aqueous solution. Taken together these observations demonstrate that, in addition to direct receptor-substrate interactions, noncovalent interactions between the two subunits of such biscyclopeptides contribute significantly to anion complex stability. Reinforcement of molecular recognition through intra-receptor interactions should be an attractive new strategy to boost host-guest affinities.


Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years.
We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0-4% of areal BMC and areal BMD variance in adults and 0-14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR(random) = 0.94; 0.72 to 1.23, I2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD(fixed) = 0.04 g/cm2 (0.00 to 0.08, P = 0.07), I2 = 0%) or FNBMD (total n = 435, MD(random) = 0.01 g/cm2 (-0.03 to 0.05, P = 0.59), I2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8-1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.


Diagnosis and management of hereditary angioedema (HAE).
In summary, HAE is a dominantly inherited form of angioedema which is manifested by nonpainful, nonerythematous, nonpruritic and nonpitting swelling of the extremities, face, gastrointestinal and respiratory tracts unaccompanied by urticaria. These patients have deficient activity of the C1 INH and the laboratory diagnosis can be easily made by finding low C4 and C1 inh levels during an attack. Effective and specific therapy is now available that prevents the clinical syndrome and corrects the serologic hallmarks of the disease.


Paradox lost? Exploring the role of alpha oscillations during externally vs. internally directed attention and the implications for idling and inhibition hypotheses.
Although slow waves of the electroencephalogram (EEG) have been associated with attentional processes, the functional significance of the alpha component in the EEG (8.1-12 Hz) remains uncertain. Conventionally, synchronisation in the alpha frequency range is taken to be a marker of cognitive inactivity, i.e. 'cortical idling'. However, it has been suggested that alpha may index the active inhibition of sensory information during internally directed attentional tasks such as mental imagery. More recently, this idea has been amended to encompass the notion of alpha synchronisation as a means of inhibition of non-task relevant cortical areas irrespective of the direction of attention. Here we test the adequacy of the one idling and two inhibition hypotheses about alpha. In two experiments we investigated the relation between alpha and internally vs. externally directed attention using mental imagery vs. sensory-intake paradigms. Results from both experiments showed a clear relationship between alpha and both attentional factors and increased task demands. At various scalp sites alpha amplitudes were greater during internally directed attention and during increased load, results incompatible with alpha reflecting cortical idling and more in keeping with suggestions of active inhibition necessary for internally driven mental operations.


A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected].
Hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders for which >/=14 different genetic loci have been identified. In some SCA types, expanded tri- or pentanucleotide repeats have been identified, and the length of these expansions correlates with the age at onset and with the severity of the clinical phenotype. In several other SCA types, no genetic defect has yet been identified. We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. Our observations are in accordance with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14-knockout mice. As indicated by protein modeling, the amino acid change from phenylalanine to serine at position 145 is predicted to reduce the stability of the protein. The present FGF14 mutation represents a novel gene defect involved in the neurodegeneration of cerebellum and basal ganglia.


Rogue wave spectra of the Kundu-Eckhaus equation.
In this paper we analyze the rogue wave spectra of the Kundu-Eckhaus equation (KEE). We compare our findings with their nonlinear Schrödinger equation (NLSE) analogs and show that the spectra of the individual rogue waves significantly differ from their NLSE analogs. A remarkable difference is the one-sided development of the triangular spectrum before the rogue wave becomes evident in time. Also we show that increasing the skewness of the rogue wave results in increased asymmetry in the triangular Fourier spectra. Additionally, the triangular spectra of the rogue waves of the KEE begin to develop at earlier stages of their development compared to their NLSE analogs, especially for larger skew angles. This feature may be used to enhance the early warning times of the rogue waves. However, we show that in a chaotic wave field with many spectral components the triangular spectra remain as the main attribute as a universal feature of the typical wave fields produced through modulation instability and characteristic features of the KEE's analytical rogue wave spectra may be suppressed in a realistic chaotic wave field.


General Northern English. Exploring Regional Variation in the North of England With Machine Learning.
In this paper, we present a novel computational approach to the analysis of accent variation. The case study is dialect leveling in the North of England, manifested as reduction of accent variation across the North and emergence of General Northern English (GNE), a pan-regional standard accent associated with middle-class speakers. We investigated this instance of dialect leveling using random forest classification, with audio data from a crowd-sourced corpus of 105 urban, mostly highly-educated speakers from five northern UK cities: Leeds, Liverpool, Manchester, Newcastle upon Tyne, and Sheffield. We trained random forest models to identify individual northern cities from a sample of other northern accents, based on first two formant measurements of full vowel systems. We tested the models using unseen data. We relied on undersampling, bagging (bootstrap aggregation) and leave-one-out cross-validation to address some challenges associated with the data set, such as unbalanced data and relatively small sample size. The accuracy of classification provides us with a measure of relative similarity between different pairs of cities, while calculating conditional feature importance allows us to identify which input features (which vowels and which formants) have the largest influence in the prediction. We do find a considerable degree of leveling, especially between Manchester, Leeds and Sheffield, although some differences persist. The features that contribute to these differences most systematically are typically not the ones discussed in previous dialect descriptions. We propose that the most systematic regional features are also not salient, and as such, they serve as sociolinguistic regional indicators. We supplement the random forest results with a more traditional variationist description of by-city vowel systems, and we use both sources of evidence to inform a description of the vowels of General Northern English.


Structural modification of nanocrystalline ceria by ion beams.
Exceptional size-dependent electronic-ionic conductivity of nanostructured ceria can significantly alter materials properties in chemical, physical, electronic and optical applications. Using energetic ions, we have demonstrated effective modification of interface volume and grain size in nanocrystalline ceria from a few nm up to ∼25 nm, which is the critical region for controlling size-dependent material property. The grain size increases and follows an exponential law as a function of ion fluence that increases with temperature, while the cubic phase is stable under the irradiation. The unique self-healing response of radiation damage at grain boundaries is utilized to control the grain size at the nanoscale. Structural modification by energetic ions is proposed to achieve desirable electronic-ionic conductivity.


Liquid chromatographic determination of residual isocyanate monomers in plastics intended for food contact use.
A liquid chromatographic (LC) method was developed for the analysis of 10 isocyanates in polyurethane articles and laminates intended for food use. Residual isocyanates are extracted by dichloromethane with concurrent derivatization by 9-(methylaminomethyl)anthracene. The resultant derivatives are analyzed by reversed-phase LC with fluorescence detection. Separation of the isocyanates was studied and optimized. Quantitation uses 1-naphthyl isocyanate as internal standard and standard addition to the food package. Validation demonstrated the method to have good precision (+/- 2-5%) and recovery (83-95%) for samples spiked with isocyanates at 0.1 mg/kg. The limit of detection was 0.03 mg/kg. Analysis of 19 commercial polyurethane or laminate food packages demonstrated that the method was not prone to interferences. Residues of diphenylmethane-4,4'-diisocyanate were detected in 5 packages and ranged from 0.14 to 1.08 mg/kg.


Normalizing acronyms and abbreviations to aid patient understanding of clinical texts: ShARe/CLEF eHealth Challenge 2013, Task 2.
The ShARe/CLEF eHealth challenge lab aims to stimulate development of natural language processing and information retrieval technologies to aid patients in understanding their clinical reports. In clinical text, acronyms and abbreviations, also referenced as short forms, can be difficult for patients to understand. For one of three shared tasks in 2013 (Task 2), we generated a reference standard of clinical short forms normalized to the Unified Medical Language System. This reference standard can be used to improve patient understanding by linking to web sources with lay descriptions of annotated short forms or by substituting short forms with a more simplified, lay term. In this study, we evaluate 1) accuracy of participating systems' normalizing short forms compared to a majority sense baseline approach, 2) performance of participants' systems for short forms with variable majority sense distributions, and 3) report the accuracy of participating systems' normalizing shared normalized concepts between the test set and the Consumer Health Vocabulary, a vocabulary of lay medical terms. The best systems submitted by the five participating teams performed with accuracies ranging from 43 to 72 %. A majority sense baseline approach achieved the second best performance. The performance of participating systems for normalizing short forms with two or more senses with low ambiguity (majority sense greater than 80 %) ranged from 52 to 78 % accuracy, with two or more senses with moderate ambiguity (majority sense between 50 and 80 %) ranged from 23 to 57 % accuracy, and with two or more senses with high ambiguity (majority sense less than 50 %) ranged from 2 to 45 % accuracy. With respect to the ShARe test set, 69 % of short form annotations contained common concept unique identifiers with the Consumer Health Vocabulary. For these 2594 possible annotations, the performance of participating systems ranged from 50 to 75 % accuracy. Short form normalization continues to be a challenging problem. Short form normalization systems perform with moderate to reasonable accuracies. The Consumer Health Vocabulary could enrich its knowledge base with missed concept unique identifiers from the ShARe test set to further support patient understanding of unfamiliar medical terms.


Methods in clonal analysis and applications.
During development, embryonic cells display a large variety of behaviors that lead to the formation of embryonic structures that are frequently transient. Simultaneously, cells progress towards a specific fate. The current challenge for embryologists is to resolve how these two distinct aspects of development co-exist. As cell behaviors (including elementary cellular operations such as motility, adhesiveness, polarization, change in shape, division and death) and their control are much less well understood than the genetic aspects of cell fate determination, there is currently much interest in the study of cell behaviors. This mainly consists of labeling groups of cells or, less frequently, single cells and observing their descendants. In this review, we describe a few techniques for labeling groups of cells and we discuss prospective and retrospective clonal analysis, in particular the LaacZ system, in detail. We examine the information generated by these approaches.


Stall in fertility decline in Eastern African countries: regional analysis of patterns, determinants and implications.
We use data from the Demographic and Health Surveys to examine the patterns of stall in fertility decline in four Eastern African countries. Contrary to patterns of fertility transition in Africa that cut across various socio-economic and geographical groups within countries, we find strong selectivity of fertility stall across different groups and regions in all four countries. In both Kenya and Tanzania where fertility decline has stalled at the national level, it continued to decline among the most educated women and in some regions. While fertility has remained at pre-transition level in Uganda over the past 20 years, there are signs of decline with specific groups of women (especially the most educated, urban and those in the Eastern region) taking the lead. For Zimbabwe, although fertility has continued to decline at the national level, stall is observed among women with less than secondary education and those in some of the regions. We link these intra-country variations to differential changes in socio-economic variables, family planning programme environment and reproductive behaviour models. The results suggest that declines in contraceptive use, increases in unmet need for family planning, increasing preferences for larger families, and increases in adolescent fertility were consistently associated with stalls in subgroup fertility across all four countries. These results are consistent with models that emphasize the role of declines in national and international commitments to family planning programmes in the premature stall in sub-Saharan fertility transition.


Cytokine production in children with tuberculous infection and disease.
To determine if the manifestations of initial infection with Mycobacterium tuberculosis reflect changes in the balance of T cell cytokines, we evaluated cytokine production by M. tuberculosis-stimulated peripheral blood mononuclear cells (PBMCs) from 24 children with tuberculosis and 22 children who were healthy tuberculin reactors. PBMCs from patients with tuberculosis had lower production and mRNA expression of interferon gamma (IFN-gamma) than did PBMCs from healthy tuberculin reactors. IFN-gamma production was most severely depressed in patients with moderately advanced and far-advanced pulmonary disease and in malnourished patients. Production of IL-12, IL-4, and IL-10 was similar in tuberculosis patients and healthy tuberculin reactors. These results indicate that, during the initial immune response to M. tuberculosis, development of tuberculosis is associated with diminished IFN-gamma production, which is not due to reduced production of IL-12 or enhanced production of IL-4 or IL-10.


Overloaded phase-code multiplexing for volume holographic storage.
Overloaded phase codes for volume holographic data storage are introduced. In contrast to any previous phase-code design, overloaded phase codes enable multiplexing of a number of data pages that exceeds the number of utilized reference beams. In this way the achievable data capacity can be augmented. Overloaded codes are generated by extending multilevel phase codes based on the discrete Fourier transform. We demonstrate multiplexing of 70 analog pages by means of 64 reference beams. The analysis of reconstructed digital data pages suggests that a capacity gain of up to 15% is reasonable.


Spatiotemporal dynamics of attention in visual neglect: a case study.
Patients with visual neglect are often unaware of contralesional visual stimuli. Recent studies have demonstrated non-spatial as well as spatial deficits in allocating attention in neglect patients. We examined the spatiotemporal dynamics of directing attention in a patient with neglect for visual objects appearing in the left side of space by using a version of the attentional blink paradigm. presenting two visual stimuli in succession. The first target (T1) was presented at fixation. The location of the second target (T2) and time between the two targets was varied. When T2 appeared to the left, the patient required more time between targets to identify both accurately, compared to when T2 appeared at fixation or to the right. Our findings demonstrate a spatial and temporal gradient of attention. The results are discussed with respect to current models of visual processing in visual neglect.


Antarctic, Sub-Antarctic and cold temperate echinoid database.
This database includes spatial data of Antarctic, Sub-Antarctic and cold temperate echinoid distribution (Echinodermata: Echinoidea) collected during many oceanographic campaigns led in the Southern Hemisphere from 1872 to 2010. The dataset lists occurrence data of echinoid distribution south of 35°S latitude, together with information on taxonomy (from species to genus level), sampling sources (cruise ID, sampling dates, ship names) and sampling sites (geographic coordinates and depth). Echinoid occurrence data were compiled from the Antarctic Echinoid Database (David et al. 2005a), which integrates records from oceanographic cruises led in the Southern Ocean until 2003. This database has been upgraded to take into account data from oceanographic cruises led after 2003. The dataset now reaches a total of 6160 occurrence data that have been checked for systematics reliability and consistency. It constitutes today the most complete database on Antarctic and Sub-Antarctic echinoids.


Return of the lysergamides. Part V: Analytical and behavioural characterization of 1-butanoyl-d-lysergic acid diethylamide (1B-LSD).
The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One recent addition to this series of LSD analogs is 1-butanoyl-LSD (1B-LSD), a constitutional isomer of 1-propanoyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B-LSD employing nuclear magnetic resonance spectroscopy (NMR), low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B-LSD from 1P-ETH-LAD was straightforward. LSD and other serotonergic hallucinogens induce the head-twitch response (HTR) in rats and mice, which is believed to be mediated largely by 5-HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B-LSD has LSD-like behavioral effects. 1B-LSD produced a dose-dependent increase in HTR counts, acting with ~14% (ED50 = 976.7 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B-LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B-LSD serves as a pro-drug for LSD. Further investigations are warranted to confirm whether 1B-LSD produces LSD-like psychoactive effects in humans.


HBV-DNA level in blood serum as a predictor of good response to therapy with interferon-alpha-2b of patients with chronic hepatitis B.
The prevalence of hepatitis B infection in population in Poland is low and averages 1-1.5%. However, it means that about 380,000 Poles constantly or temporarily replicate HBV. Chronic HBV infection is associated with increased risk of serious liver diseases and it is estimated that 25-40% of patients with chronic hepatitis B will die prematurely of cirrhosis or primary liver cancer. Up to the present, interferon-alpha (IFN-alpha), with low response rate between 25-55% and some limitations of therapy, has been the only available treatment for chronic hepatitis B. A favorable outcome of IFN-alpha therapy is associated with some prognostic factors, not accepted by all investigators, such as low level of HBV-DNA in serum. The aim of this study was to assess the efficacy of therapy with IFN-alpha 2b (Intron A), administered s.c. 5 MU x 3/week for 16 weeks, in 65 patients with chronic hepatitis B, divided into groups according to the baseline HBV-DNA level. Except for serum HBV-DNA level, there were no demographical and biochemical differences between all the treated groups. The patients were followed-up for 12 months. Sustained response (SR) to the therapy (defined as ALAT normalization, loss of detectable HBV-DNA, seroconversion HBeAg to anti-HBeAg and improvement in liver histology) was observed in 16 (57.14%) of patients in the group with HBVDNA level < 1000 pg/ml, in 6 (37.5%) with HBV-DNA level of 1001-3000 pg/ml, in 4 (28.57%) with HBV-DNA level of 3001-5000 pg/ml and only in 2 (28.57%) of patients in group with HBVDNA level > 5000 pg/ml. We conclude that IFN-alpha is particularly useful in therapy of patients with chronic hepatitis B with low levels of HBV-DNA. The baseline HBVDNA level < 1000 pg/ml in serum is the predictor of good response to IFN-alpha therapy.


An unusual infection outbreak in rats held in a human hospital research laboratory.
Most animal hazards in laboratories are widely recognized. These, together with zoonoses and other possible insults, are subject to the establishment of guidelines for the operation and maintenance of such facilities. Most of the infectious diseases described among laboratory animals are related to the inadequate implementation of preventive and quality control policies. These included surgical, respiratory and intestinal tract infections, and typically spread between animals. This report is about an outbreak of nosocomial bacterial infection in rats held in the research laboratory of a human hospital. Symptoms of general infection were runny nose and sneezing, excessive lachrymation, dyspnea, loss of appetite, limited activity and disheveled fur, which appeared in two rats initially, and spread to another 60. A common characteristic physical finding observed later was a lump under the skin, with subsequent ulceration. Mortality was 70%. Blood cultures were sterile. Accurate diagnosis was possible only after examination of tissue sampled from the diseased and dead rats. Histology showed an excessive proliferative and inflammatory reaction. Bacteriology analysis revealed the presence of three types of hospital-borne bacteria: enterococcus, coagulase-negative staphylococci and Acinetobacter radioresistens, with common sensitivity to ciprofloxacin and ceftazidime. Empiric antibiotic therapy was switched to a bacteriology-based regimen. Complete recovery was achieved among the diseased rats that survived the previous antibiotic therapy. This is the first written description of a nosocomial infection of laboratory animals caused by bacteria borne in a human hospital. Medical staff-to-animal transmission is suggested. A high index of suspicion and prompt diagnostic evaluation are essential for successful management, and preventive guidelines concerning such events need to be established.