'As a clinician, you are not managing lab results, you are managing the patient': how the enactment of malaria at health facilities in Cameroon compares with new WHO guidelines for the use of malaria tests.
In response to widespread overuse of antimalarial drugs, the World Health Organisation changed guidelines in 2010 to restrict the use of antimalarials to parasitologically confirmed malaria cases. Malaria rapid diagnostic tests (RDTs) have been presented as a means to realize the new guidelines, and National Malaria Control Programmes, including that of Cameroon, are developing plans to introduce the tests to replace microscopy or clinical diagnosis at public health facilities across the country. We aimed to understand how malaria tests and antimalarial drugs are currently used as part of social interactions between health workers and patients at public and mission health facilities in Yaoundé and Bamenda and surrounding districts in the Northwest region of Cameroon. In May to June 2010, we held 17 focus group discussions with 146 health workers involved in clinical care from 49 health facilities. Clinicians enacted malaria as a 'juggling' exercise, involving attention to pathophysiology of the patient as well as their desires and medical reputations, utilising tests and medicines for their therapeutic effects as symbols in the process of care. Parasites were rarely mentioned in describing diagnostic decisions. These enactments of malaria contrast with evidence-based guidelines emanating from WHO, which assume the parasite is the central driver of practice. If RDTs are to be taken up in practice, public health practitioners need to pay careful attention to the values and priorities of health workers and patients if they are to work with them to improve diagnosis and treatment of febrile illnesses.


Protocols in sports magnetic resonance imaging.
Magnetic resonance imaging, with its multiplanar imaging capability and superior soft-tissue contrast, has become the preferred method for imaging sports-related injuries. Advances in gradient technology, receiver coils, and imaging software have allowed the imaging of the injured athlete to take place quickly and at high resolution. Understanding the tissues being imaged, the underlying anatomy, and the capabilities of today's scanners is crucial to the design of intelligent and efficient protocols.


Individual differences in working memory capacity and visual search: the roles of top-down and bottom-up processing.
Individual differences in working memory capacity (WMC) have been implicated in a variety of top-down, attention-control tasks: Higher WMC subjects better ignore irrelevant distractions and withhold habitual responses than do lower WMC subjects. Kane, Poole, Tuholski, and Engle (2006) recently attempted to extend these findings to visual search, but found no relation between WMC and search efficiency, even in difficult tasks yielding steep search slopes. Here we used a visual search task that isolated the contributions of top-down versus bottom-up mechanisms, and induced a habitual response via expectation. Searches that relied primarily on bottom-up mechanisms did not vary with WMC, but searches that relied primarily on top-down mechanisms showed an advantage for higher over lower WMC subjects.


Awareness of racial and socioeconomic health disparities in the United States: the national opinion survey on health and health disparities, 2008-2009.
Recent initiatives aim to improve public awareness of health disparities. However, little research has actually documented the US public's awareness of racial/ethnic and socioeconomic health disparities. We sought to determine 1) whether the US public is aware of racial, educational, and income disparities in health, 2) whether awareness differs across these disparity domains, and 3) what respondent characteristics are associated with awareness of racial, educational, and income disparities in health. We conducted the National Opinion Survey on Health and Health Disparities with 2,791 US adults. We asked respondents to answer questions about disparities in health between 1 of several pairs of population subgroups: African Americans versus whites, non-high school graduates versus high school graduates, high school graduates versus college graduates, the poor versus the middle class, or the middle class versus the rich. We used χ(2) tests and logistic regression to compare correlates of respondents' awareness of disparities across the different pairs of population subgroups. Most respondents were aware of health disparities between the poor and middle class (73%); fewer were aware of health disparities between African Americans and whites (46%). Although respondents recognized that education is associated with many positive life outcomes, they were less aware of the link between education and health. Respondents who were younger, less educated, lower-income, healthier, or politically conservative were less likely to be aware of health disparities. Public awareness of disparities in health differs depending on both the type of disparity and the characteristics of the individual respondent.


Topology highlights mesoscopic functional equivalence between imagery and perception: The case of hypnotizability.
The functional equivalence (FE) between imagery and perception or motion has been proposed on the basis of neuroimaging evidence of large spatially overlapping activations between real and imagined sensori-motor conditions. However, similar local activation patterns do not imply the same mesoscopic integration of brain regions, which can be described by tools from Topological Data Analysis (TDA). On the basis of behavioral findings, stronger FE has been hypothesized in the individuals with high scores of hypnotizability scores (highs) with respect to low hypnotizable participants (lows) who differ between each other in the proneness to modify memory, perception and behavior according to specific imaginative suggestions. Here we present the first EEG evidence of stronger FE in highs. In fact, persistent homology shows that the highs EEG topological asset during real and imagined sensory conditions is significantly more similar than the lows. As a corollary finding, persistent homology shows lower restructuring of the EEG asset in highs than in lows during both sensory and imagery tasks with respect to basal conditions. Present findings support the view that greater embodiment of mental images may be responsible for the highs greater proneness to respond to sensori-motor suggestions and to report involuntariness in action. In addition, findings indicate hypnotizability-related sensory and cognitive information processing and suggest that the psycho-physiological trait of hypnotizability may modulate more than one aspect of the everyday life.


Gd(III)-PyMTA label is suitable for in-cell EPR.
Distance measurement in the nanometer range by electron paramagnetic resonance spectroscopy (EPR) in combination with site-directed spin labeling is a very powerful tool to monitor the structure and dynamics of biomacromolecules in their natural environment. However, in-cell application is hampered by the short lifetime of the commonly used nitroxide spin labels in the reducing milieu inside a cell. Here, we demonstrate that the Gd(III) based spin label Gd-PyMTA is suitable for in-cell EPR. Gd-PyMTA turned out to be cell compatible and was proven to be inert in in-cell extracts of Xenopus laevis oocytes at 18 °C for more than 24 h. The proline rich peptide H-AP10CP10CP10-NH2 was site-directedly spin labeled with Gd-PyMTA at both cysteine moieties. The resulting peptide, H-AP10C(Gd-PyMTA)P10C(Gd-PyMTA)P10-NH2, as well as the model compound Gd-spacer-Gd, which consists of a spacer of well-known stiffness, were microinjected into Xenopus laevis oocytes, and the Gd(III)-Gd(III) distances were determined by double electron-electron resonance (DEER) spectroscopy. To analyze the intracellular peptide conformation, a rotamer library was set up to take the conformational flexibility of the tether between the Gd(III) ion and the Cα of the cysteine moiety into account. The results suggest that the spin labeled peptide H-AP10C(Gd-PyMTA)P10C(Gd-PyMTA)P10-NH2 is inserted into cell membranes, coinciding with a conformational change of the oligoproline from a PPII into a PPI helix.


Stable micelles based on a mixture of coiled-coils: the role of different oligomeric states.
Homomeric micelles with tunable size, shape and stability have been extensively studied for biomedical applications such as drug carriers. However, designing the local valency and self-assembled morphology of nanophase-separated multicomponent micelles with varied ligand binding possibilities remains challenging. Here, we present micelles self-assembled from amphiphilic peptide-PEG-lipid hybrid conjugates, where the peptides can be either a 3-helix or 4-helix coiled-coil. We demonstrate that the micelle size and sphericity can be controlled based on the coiled-coil oligomeric state. Using theory and coarse-grained dissipative particle dynamics (DPD) simulations in an explicit solvent simulation, we studied the distribution of 3-helix and 4-helix conjugates within the mixed micelles and observed self-organization into nanodomains within the mixed micelle. We discovered that the phase separation behavior is dictated by the geometry mismatch in the alkyl chain length from different coiled-coil oligomeric states. Our analyses of the self-assembly tendency and drug delivery potency of mixed micelles with controlled multivalency provide important insights into the assembly and formation of nanophase-separated micelles.


BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy.
BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored. p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib. The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.


D-penicillamine causes free radical-dependent inactivation of activator protein-1 DNA binding.
D-Penicillamine (beta, beta-dimethyl cysteine) is an antirheumatic thiol drug with a poorly understood mechanism of action. On the basis that gold(I) thiolates and D-penicillamine are both capable of forming stable bonds with endogenous thiols, we sought a common target of action. Cysteine residues in the basic DNA binding domains of Jun and Fos, members of the activator protein-1 (AP-1) transcription factor family, have been identified as likely targets for the therapeutic action of antirheumatic gold(I) thiolates. The current study demonstrates that AP-1 DNA binding is inhibited by D-penicillamine in the presence of Fenton reagents (Fe2+/EDTA and H2O2) but not with either agent alone. The effect is biphasic, with maximum inhibition in the concentration range of approximately 100-250 microM. Cysteine has qualitatively similar properties, although the effect is less pronounced. In contrast, glutathione and thiomalate do not inhibit AP-1 DNA binding, even in the presence of Fenton reagents. Mutant proteins were used to identify the cysteine residues within the DNA binding domains of Jun and Fos that are essential for the inhibitory action of D-penicillamine. The results suggest that D-penicillamine is distinguished from other thiols by its formation of sulfur-containing radicals capable of inhibiting AP-1 DNA binding by a mechanism involving the cysteine residues of Jun and Fos.


Autonomic control of the heart: going beyond the classical neurotransmitters.
What is the topic of this review? This symposium report discusses the evidence for release of cardiac sympathetic cotransmitters in addition to noradrenaline. What advances does it highlight? It highlights the potential role of neuropeptide Y in reducing vagal neurotransmission and directly influencing ventricular myocyte excitability in the presence of β-receptor blockade. Acute myocardial infarction and congestive cardiac failure are characterized by high levels of cardiac sympathetic drive. In these conditions, sympathetic neurotransmitters such as neuropeptide Y (NPY) can be released in addition to noradrenaline, and plasma levels correlate with infarct size and mortality. Even in the presence of β-blockers, NPY is able to bind to its own receptors located on cholinergic ganglia and ventricular myocytes. In this symposium report, I review the evidence that NPY can inhibit acetylcholine release during vagus nerve stimulation and limit the subsequent bradycardia. I also present preliminary, as yet unpublished data, demonstrating that NPY may be pro-arrhythmic by directly influencing ventricular electrophysiology. Targeting NPY receptors pharmacologically may therefore be a useful therapeutic strategy both to reduce heart rate and to prevent arrhythmias in the setting of myocardial infarction and chronic heart failure. Such medications would be expected to act synergistically with β-blockers, angiotensin-converting enzyme inhibitors and implantable cardiac devices, such as defibrillators and vagus nerve stimulators.


T cell receptor (TCR) recognition of MHC class I variants: intermolecular second-site reversion provides evidence for peptide/MHC conformational variation.
We investigated mechanistic differences in antigen presentation between murine MHC class I variants H-2K(b) and H-2K(bm)8. H-2K(bm)8 differs from H-2K(b) by four residues at the floor of the peptide-binding site, affecting its B pocket which interacts with the second (P2) residue of the peptide. The rest of the molecule, including the T cell receptor (TCR)-contacting residues, is identical to H-2K(b). Due to this variation, CTLs that recognize the ovalbumin 257-264 and HSV gB 498-505 peptides on H-2K(b) cannot recognize them on H-2K(bm)8. This could be due to impaired peptide binding or an altered peptide: K(bm)8 conformation. Peptide binding studies ruled out the first explanation. Molecular modeling indicated that the most obvious consequence of amino acid variation between peptide/H-2K(b) and peptide/H-2K(bm)8 complexes would be a loss of the conserved hydrogen bond network in the B pocket of the latter. This could cause conformational variation of bound peptides. Intermolecular second-site reversion was used to test this hypothesis: P2-substituted OVA and HSV peptides, engineered to restore the hydrogen bond network of the B pocket, were the only ones which restored CTL recognition. These results provide a molecular understanding of peptide/MHC conformational variation.


Effects of a behavioral intervention that emphasizes spices and herbs on adherence to recommended sodium intake: results of the SPICE randomized clinical trial.
For decades, dietary sodium intake in the United States has remained high, and few studies have examined strategies for maintaining recommended intakes. We examined the effects of a behavioral intervention, which emphasized spices and herbs, on the maintenance of sodium intake at the recommended intake of 1500 mg/d in individuals to whom the US Dietary Guidelines for Americans apply. We conducted a 2-phase study that included adults ≥18 y of age for whom Dietary Guidelines for Americans recommends 1500 mg Na/d. The study was conducted in Baltimore, Maryland, from 2012 to 2014. In phase 1, 55 individuals consumed a low-sodium diet for 4 wk. Participants were provided all foods, snacks, and calorie-containing drinks. In phase 2, 40 participants from phase 1 were randomly assigned to either a behavioral intervention to reduce sodium intake (n = 20) or a self-directed control group (n = 20) for 20 wk. The primary study outcome was the change in mean 24-h urinary sodium excretion during phase 2. Linear regression analyses were used to determine intervention effects on urinary sodium excretion. Participant characteristics were as follows: women: 65%; African American: 88%; hypertension: 63%; diabetes: 18%; mean age: 61 y; and mean body mass index (in kg/m(2)): 30. At the end of phase 2, mean 24-h sodium excretion was lower in the behavioral intervention than in the self-directed group (mean difference: -956.8 mg/d; 95% CI: -1538.7, -374.9 mg/d) after sodium intake at screening was controlled for (P = 0.002). These findings persisted in sensitivity analyses that excluded potentially incomplete urine collections [Mage's equation mean difference: -1090 mg/d (P = 0.001); Joosens' equation mean difference: -796 mg/d (P = 0.04)]. A multifactorial behavioral intervention emphasizing spices and herbs significantly reduced sodium intake. Because of the ubiquity of sodium in the US food supply, multilevel strategies addressing individual behaviors and the food supply are needed to improve adherence to recommendations. This trial was registered at clinicaltrials.gov as NCT01615159.


Ethyl Formate: A Potential Disinfestation Treatment for Eucalyptus Weevil (Gonipterus platensis) (Coleoptera: Curculionidae) in Apples.
Export of Pink Lady apples from Australia has been significantly affected by infestations of adult eucalyptus weevils (Gonipterus platensis Marelli). These weevils cling tenaciously to the pedicel of apple fruit when selecting overwintering sites. As a result, apples infested with live G. platensis adults lead to rejection for export. Since the Montreal Protocol restricted use of methyl bromide as postharvest treatment, it was necessary to consider alternative safer fumigants for disinfestation of eucalyptus weevil. Laboratory experiments were conducted using concentrations of 5, 10, 15, 20, 25, 30, 40, and 80 mg/liter of ethyl formate. Complete control (100% mortality) was achieved at 25-30 mg/liter of ethyl formate at 22-24°C for 24-h exposure without apples. However, with 90-95% of the volume full of apples, complete control was achieved at 40 mg/liter of ethyl formate at 22-24°C for 24-h exposure. No phytotoxicity was observed and after one day aeration, residue of ethyl formate declined to natural levels (0.05-0.2 mg/kg). Five ethyl formate field trials were conducted in cool storages (capacity from 250-900 tons) and 100% kill of eucalyptus weevils were achieved at 50-55 mg/liter at 7-10°C for 24 h. Ethyl formate has great potential for preshipment treatment of apples. Its use is considerably cheaper and safer than already existing fumigants like methyl bromide and phosphine.


A population-based approach to assess the heritability and distribution of renal handling of electrolytes.
The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population.


Expression of the mouse alpha 1(II) collagen gene is not restricted to cartilage during development.
The mouse alpha 1(II) collagen gene has been isolated and a 5' portion of the gene which has low homology to other collagen genes was used to study the pattern of expression during mouse embryogenesis. In situ hybridization studies show that in the mouse, like the chick, alpha 1(II) collagen is expressed in chondrogenic tissues in advance of chondrocyte differentiation. The gene is expressed early in embryogenesis at 9.5 days both in the cranial mesenchyme destined for the chondrocranium, and the sclerotome of the somites, and at 12.5 days in the primordia of the hyoid and the laryngeal cartilage. Type II collagen gene transcripts were found in all the chondrogenic tissues of the axial and appendicular skeleton until the onset of endochondral ossification. Expression of alpha 1(II) collagen mRNA was also observed in non-chondrogenic tissues such as the notochord which may be responsible for inducing chondrogenesis in somitic mesoderm, neural retina, the corneal and conjunctival epithelia and sclera of the developing eye. Expression in the tail tendon was late, at 16.5-18.5 days. Transient expression was also found in the heart at 9.5-12.5 days, the epidermis at 10.5-14.5 days, the calvarial mesenchyme at 12.5-16.5 days, the inner ear at 14.5 days and the fetal brain from 9.5-14.5 days. Within the neural tube, alpha 1(II) collagen mRNA was localized in the proliferative ventricular cells of the forebrain and midbrain of 9.5- to 10.5-day embryos. Subsequently, transcription of the alpha 1(II) collagen gene was confined to restricted areas of the rhombencephalic basal plate, the ventricular layer of the hindbrain and the cervical spinal cord. These examples of expression of the type II collagen gene in the developing nervous system seem to suggest that active transcription of this gene might be associated with early stages of neuroblast differentiation. Type II collagen may therefore have additional roles in development unrelated to chondrogenesis.


Single-Cell RNA-Seq of Bone Marrow-Derived Mesenchymal Stem Cells Reveals Unique Profiles of Lineage Priming.
The plasticity and immunomodulatory capacity of mesenchymal stem cells (MSCs) have spurred clinical use in recent years. However, clinical outcomes vary and many ascribe inconsistency to the tissue source of MSCs. Yet unconsidered is the extent of heterogeneity of individual MSCs from a given tissue source with respect to differentiation potential and immune regulatory function. Here we use single-cell RNA-seq to assess the transcriptional diversity of murine mesenchymal stem cells derived from bone marrow. We found genes associated with MSC multipotency were expressed at a high level and with consistency between individual cells. However, genes associated with osteogenic, chondrogenic, adipogenic, neurogenic and vascular smooth muscle differentiation were expressed at widely varying levels between individual cells. Further, certain genes associated with immunomodulation were also inconsistent between individual cells. Differences could not be ascribed to cycles of proliferation, culture bias or other cellular process, which might alter transcript expression in a regular or cyclic pattern. These results support and extend the concept of lineage priming of MSCs and emphasize caution for in vivo or clinical use of MSCs, even when immunomodulation is the goal, since multiple mesodermal (and even perhaps ectodermal) outcomes are a possibility. Purification might enable shifting of the probability of a certain outcome, but is unlikely to remove multilineage potential altogether.


Towards a structural understanding of drug and peptide transport within the proton-dependent oligopeptide transporter (POT) family.
One of the principal aims of modern drug design is the targeted delivery of drugs within the body, such as to the central nervous system, combined with their exclusion from the liver and kidneys, which break down foreign molecules and subsequently eliminate them. Many of the commonly prescribed drugs are transported into cells and across the plasma membrane via endogenous membrane transporters, whose principal roles are the uptake of essential nutrients for metabolism. In many cases, such drug transport is serendipitous as they are simply mistaken as 'natural' compounds. Many of these transporters could, however, be targeted more efficiently, improving drug absorption, distribution and retention. The molecular details of these drug-transporter interactions, however, are at best poorly understood, in large part through the absence of any high-resolution structural information. To address this issue, we recently determined the structure of a prokaryotic peptide transporter, PepTSo from Shewanella oneidensis, which shares a high degree of sequence similarity and functional characteristics with the human PepT1 and PepT2 proteins. PepT1 and PepT2 contribute significantly to the oral bioavailability and pharmacokinetic properties of a number of important drug families, including antibiotics, antivirals and anticancer agents. The crystal structure of PepTSo provides the first high-resolution model of a drug importer and provides the starting point for understanding drug and peptide transport within the human body.


Cellular alterations in midgut cells of honey bee workers (Apis millefera L.) exposed to sublethal concentrations of CdO or PbO nanoparticles or their binary mixture.
Beside many beneficial applications in industry, agriculture and medicine, nanoparticles (NPs) released into the environment might cause adverse effects. In the present study, effects of exposure to sublethal concentrations of PbO and CdO NPs, either separately or in combination on honey bee (A. mellifera) workers were assessed. Honey bee workers were fed sugar syrup contained (20% of LC50) of CdO (0.01 mg ml-1) and PbO (0.65 mg ml-1) NPs either separately or combined for nine days under laboratory conditions. Control bees were fed 1.5 M sucrose syrup without NPs. Effects on histological and cellular structure of mid gut cells were investigated using light and electron microscope. Percentages of incidence of apoptosis or/and necrosis in mid gut cells were also quantified by use of flow cytometry. Rapture of the peritrophic membrane (PM) was among the most observed histopathological alteration in bees fed sugar syrup contained CdO NPs separately or combined with PbO NPs. Common cytological alterations observed in epithelial cells were irregular distribution or/and condensation of nuclear chromatin, mitochondrial swelling and lysis, and rough endoplasmic reticulum (rER) dilation, fragmentation, and vesiculation and were quite similar in all treated groups compared to control. The greatest incidence (%) of necrosis was observed in bees fed the diet that contained CdO NPs alone. The greatest % of both apoptosis and necrosis was observed in bees fed sugar syrup spiked with sublethal concentrations of both metal oxide NPs. Joint action of the binary mixture of Cd and Pb oxide NPs on honey bees was concluded to be antagonistic. Collectively, exposure of honey bees to these metal oxide NPs even at sublethal concentrations will adversely affect viability of the colony and further studies are still required to determine the effects of these metal oxide NPs on behavior and pollination ecology of honeybees.


Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for β-Cell Imaging.
Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of β-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on β-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used β-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful β-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis.


Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians.
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians. The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance. A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance. Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.


Narrating the generative life.
Generativity is an adult's concern for and commitment to promoting the well-being of future generations. Analyzing lengthy life-narrative interviews of late-midlife adults, we examined the extent to which a particular kind of life story is empirically linked to self-report measures of generativity and other indices of psychosocial adaptation in midlife. The results showed that highly generative adults are significantly more likely than their less-generative counterparts to construe their lives as variations on a prototypical redemption narrative, wherein the story's protagonist (a) enjoys an early advantage in life, (b) exhibits sensitivity to the suffering of other people, (c) develops a clear moral framework, (d) repeatedly transforms negative scenes into positive outcomes, and (e) pursues prosocial goals for the future. The psychological and cultural features of redemptive life stories are considered, as are the problems and potentialities of life-narrative research in psychological science.


Risk factors for childhood violence and polyvictimization: A cross-country analysis from three regions.
Understanding risk factors is important to ending childhood violence and meeting Sustainable Development Goal 16.2. To date, no study has examined patterns of risk factors across countries comprehensively for different types of childhood violence, and there is a dearth of evidence of polyvictimization in lower- and middle-income settings. We analyse risk factors of childhood emotional (EV), physical (PV), sexual violence (SV) and polyvictimization for children aged 13-17 from nationally-representative Violence Against Children Surveys across six countries. We examine risk factors at the community-, household-, and individual- levels for each violence type, stratified by gender using multivariable logistic regression models. Across countries, school enrolment increased violence risk among females and males (three countries), but was protective against violence among females (one country), and among males (three countries). Among females, increasing age was associated with increased risk of SV (five countries) and polyvictimization (three countries); among males this relationship was less salient. Non-residence with a biological father emerged as a risk factor for SV among girls. Few or inconsistent associations were found with other factors, including number of household members, wealth, and urban residence. These results underscore on the one hand, the need for country-specific research on risk factors to inform prevention strategies, as well as increased investment in data collection to provide a more complete and robust basis for evidence generation. High levels of polyvictimization highlight overlapping vulnerabilities children face, and may provide insights for policymakers and practitioners in designing strategies to protect children at greatest risk of abuse.


Objectively Measured Changes in Physical Activity and Sedentary Behavior in Cardiac Rehabilitation: A PROSPECTIVE COHORT STUDY.
Physical inactivity and sedentary behavior (SB) are independent risk factors for cardiovascular disease and all-cause mortality. No studies appear to have investigated whether SB in cardiac rehabilitation (CR) participants changes over time. The aim of this study was to objectively assess physical activity (PA) and SB of CR participants over 6 wks. Using a prospective cohort study design, 72 CR participants, age = 64.2 ± 9.6 y (mean ± standard deviation [SD]) (79% male), wore an ActiGraph ActiSleep accelerometer for 7 consecutive days at the beginning and end of a 6-wk program to assess daily minutes of moderate-to-vigorous PA (MVPA) and SB (<100 counts/min). Other outcomes collected were self-reported MVPA (Active Australia Survey) and SB (Past-Day Adults' Sedentary Time Questionnaire), body mass index, waist-to-hip ratio, lipid profile, blood glucose level, quality of life (MacNew), exercise capacity (6-min walk test), anxiety and depression (Hospital Anxiety and Depression Scale). Time spent in MVPA and SB did not change over 6 wks. However, exercise capacity and light-intensity PA significantly improved (P < .01). On average, participants spent 11.8 ± 1.1 hr daily in SB, with 9.5 ± 14.7 min daily in MVPA at the end of the CR program. There was some evidence that males and females had different movement patterns. Levels of PA are low and SB is high in CR participants despite changes in exercise capacity over 6 wks. Participants in CR did increase their PA but only in the light-intensity range. Alternative approaches in CR should be considered to encourage participants to move more and sit less.


Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells.
The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction. It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. In developing and mature sensory hair cells, stereocilia are connected to each other by various types of fibrous links. Two unconventional cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels. These proteins also form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The proteins involved in anchoring these diverse links to the stereocilia dense actin cytoskeleton remain largely unknown. We show that the long isoform of whirlin (L-whirlin), a PDZ domain-containing submembrane scaffold protein, is present at the tips of the tall stereocilia in mature hair cells, together with PCDH15 isoforms CD1 and CD2; L-whirlin localization to the ankle-link region in developing hair bundles moreover depends on the presence of PCDH15-CD1 also localizing there. We further demonstrate that L-whirlin binds to PCDH15 and CDH23 with moderate-to-high affinities in vitro. From these results, we suggest that L-whirlin is part of the molecular complexes bridging PCDH15-, and possibly CDH23-containing lateral links to the cytoskeleton in immature and mature stereocilia.


Establishing a definition of polar bear (Ursus maritimus) health: a guide to research and management activities.
The meaning of health for wildlife and perspectives on how to assess and measure health, are not well characterized. For wildlife at risk, such as some polar bear (Ursus maritimus) subpopulations, establishing comprehensive monitoring programs that include health status is an emerging need. Environmental changes, especially loss of sea ice habitat, have raised concern about polar bear health. Effective and consistent monitoring of polar bear health requires an unambiguous definition of health. We used the Delphi method of soliciting and interpreting expert knowledge to propose a working definition of polar bear health and to identify current concerns regarding health, challenges in measuring health, and important metrics for monitoring health. The expert opinion elicited through the exercise agreed that polar bear health is defined by characteristics and knowledge at the individual, population, and ecosystem level. The most important threats identified were in decreasing order: climate change, increased nutritional stress, chronic physiological stress, harvest management, increased exposure to contaminants, increased frequency of human interaction, diseases and parasites, and increased exposure to competitors. Fifteen metrics were identified to monitor polar bear health. Of these, indicators of body condition, disease and parasite exposure, contaminant exposure, and reproductive success were ranked as most important. We suggest that a cumulative effects approach to research and monitoring will improve the ability to assess the biological, ecological, and social determinants of polar bear health and provide measurable objectives for conservation goals and priorities and to evaluate progress.


Lifestyle physical activity among urban Palestinians and Israelis: a cross-sectional comparison in the Palestinian-Israeli Jerusalem risk factor study.
Urban Palestinians have a high incidence of coronary heart disease, and alarming prevalences of obesity (particularly among women) and diabetes. An active lifestyle can help prevent these conditions. Little is known about the physical activity (PA) behavior of Palestinians. This study aimed to determine the prevalence of insufficient PA and its socio-demographic correlates among urban Palestinians in comparison with Israelis. An age-sex stratified random sample of Palestinians and Israelis aged 25-74 years living in east and west Jerusalem was drawn from the Israel National Population Registry: 970 Palestinians and 712 Israelis participated. PA in a typical week was assessed by the Multi-Ethnic Study of Atherosclerosis (MESA) questionnaire. Energy expenditure (EE), calculated in metabolic equivalents (METs), was compared between groups for moderate to vigorous-intensity physical activity (MVPA), using the Wilcoxon rank-sum test, and for domain-specific prevalence rates of meeting public health guidelines and all-domain insufficient PA. Correlates of insufficient PA were assessed by multivariable logistic modeling. Palestinian men had the highest median of MVPA (4740 METs-min*wk-1) compared to Israeli men (2,205 METs-min*wk-1 p < 0.0001), or to Palestinian and Israeli women, who had similar medians (2776 METs-min*wk-1). Two thirds (65%) of the total MVPA reported by Palestinian women were derived from domestic chores compared to 36% in Israeli women and 25% among Palestinian and Israeli men. A high proportion (63%) of Palestinian men met the PA recommendations by occupation/domestic activity, compared to 39% of Palestinian women and 37% of the Israelis. No leisure time PA was reported by 42% and 39% of Palestinian and Israeli men (p = 0.337) and 53% and 28% of Palestinian and Israeli women (p < 0.0001). Palestinian women reported the lowest level of walking. Considering all domains, 26% of Palestinian women were classified as insufficiently active versus 13% of Palestinian men (p < 0.0001) who did not differ from the Israeli sample (14%). Middle-aged and elderly and less educated Palestinian women, and unemployed and pensioned Palestinian men were at particularly high risk of inactivity. Socio-economic indicators only partially explained the ethnic disparity. Substantial proportions of Palestinian women, and subgroups of Palestinian men, are insufficiently active. Culturally appropriate intervention strategies are warranted, particularly for this vulnerable population.


Subunit-specific phenotypes of Salmonella typhimurium HU mutants.
Salmonella hupA and hupB mutants were studied to determine the reasons for the high degree of conservation in HU structure in bacteria. We found one HU-1-specific effect; the F'128 plasmid was 25-fold less stable in hupB compared with hupA or wild-type cells. F' plasmids were 120-fold more unstable in hupA hupB double mutants compared with wild-type cells, and the double mutant also had a significant alteration in plasmid DNA structure. pBR322 DNA isolated from hupA hupB strains was deficient in supercoiling by 10 to 15% compared with wild-type cells, and the topoisomer distribution was significantly more heterogeneous than in wild-type or single-mutant strains. Other systems altered by HU inactivation included flagellar phase variation and phage Mu transposition. However, Mu transposition rates were only about fourfold lower in Salmonella HU double mutants. One reason that Salmonella HU double mutants may be less defective for Mu transposition than E. coli is the synthesis in double mutants of a new, small, basic heat-stable protein, which might partially compensate for the loss of HU. The results indicate that although either HU-1 or HU-2 subunit alone may accommodate the cellular need for general chromosomal organization, the selective pressure to conserve HU-1 and HU-2 structure during evolution could involve specialized roles of the individual subunits.


'Where' and 'what' in visual search.
A line segment target can be detected among distractors of a different orientation by a fast 'preattentive' process. One view is that this depends on detection of a 'feature gradient', which enables subjects to locate where the target is without necessarily identifying what it is. An alternative view is that a target can be identified as distinctive in a particular 'feature map' without subjects knowing where it is in that map. Experiments are reported in which briefly exposed arrays of line segments were followed by a pattern mask, and the threshold stimulus-mask interval determined for three tasks: 'what'--subjects reported whether the target was vertical or horizontal among oblique distractors; 'coarse where'--subjects reported whether the target was in the upper or lower half of the array; 'fine where'--subjects reported whether or not the target was in a set of four particular array positions. The threshold interval was significantly lower for the 'coarse where' than for the 'what' task, indicating that, even though localization in this task depends on the target's orientation difference, this localization is possible without absolute identification of target orientation. However, for the 'fine where' task, intervals as long as or longer than those for the 'what' task were required. It appears either that different localization processes work at different levels of resolution, or that a single localization process, independent of identification, can increase its resolution at the expense of processing speed. These possibilities are discussed in terms of distinct neural representations of the visual field and fixed or variable localization processes acting upon them.


Population structure analysis and laboratory monitoring of Shigella by core-genome multilocus sequence typing.
The laboratory surveillance of bacillary dysentery is based on a standardised Shigella typing scheme that classifies Shigella strains into four serogroups and more than 50 serotypes on the basis of biochemical tests and lipopolysaccharide O-antigen serotyping. Real-time genomic surveillance of Shigella infections has been implemented in several countries, but without the use of a standardised typing scheme. Here, we study over 4000 reference strains and clinical isolates of Shigella, covering all serotypes, with both the current serotyping scheme and the standardised EnteroBase core-genome multilocus sequence typing scheme (cgMLST). The Shigella genomes are grouped into eight phylogenetically distinct clusters, within the E. coli species. The cgMLST hierarchical clustering (HC) analysis at different levels of resolution (HC2000 to HC400) recognises the natural population structure of Shigella. By contrast, the serotyping scheme is affected by horizontal gene transfer, leading to a conflation of genetically unrelated Shigella strains and a separation of genetically related strains. The use of this cgMLST scheme will facilitate the transition from traditional phenotypic typing to routine whole-genome sequencing for the laboratory surveillance of Shigella infections.


A pediatric digital storytelling system for third year medical students: the virtual pediatric patients.
Computer-based patient simulations (CBPS) are common, effective, instructional methods for medical students, but have limitations. The goal of this project was to describe the development of a CBPS designed to overcome some of these limitations and to perform an online evaluation. In 1996, patients and families experiencing a common pediatric problem were interviewed, photographed and a chart review completed. A digital storytelling template was developed: 1. patient's story, evaluation and clinical course, 2. problem-based approach to the evaluation, and 3. discussion of disease process. The media was digitized and placed onto the Internet. The digital stories and a 10-question online survey were pilot tested. Online survey responses were collected from 1999-2003. Overall use of the digital stories was measured by computer server logs and by the number of hyperlinks to the CBPS. Eight stories were created using this system. Over 4.5 years, 814,148 digital story pages were read by 362,351 users. Hyperlink citations from other websites to the CBPS were 108. Online survey respondents (N = 393) described the overall quality as excellent or very good (88.4%). The stores were clearly written (92%) at an appropriate level (91.4%). Respondents felt they could begin to evaluate a similar case presentation (95.4%), and would remember the case in the future (91%). A new type of CBPS, the digital storytelling system, has been developed and evaluated which and appears to be successful in overcoming some of the limitations of earlier CBPS by featuring patient's stories in their own words, by focusing on problems rather than diseases, and by having stories that are quick for students to work through.


Being immersed in social networking environment: Facebook groups, uses and gratifications, and social outcomes.
A Web survey of 1,715 college students was conducted to examine Facebook Groups users' gratifications and the relationship between users' gratifications and their political and civic participation offline. A factor analysis revealed four primary needs for participating in groups within Facebook: socializing, entertainment, self-status seeking, and information. These gratifications vary depending on user demographics such as gender, hometown, and year in school. The analysis of the relationship between users' needs and civic and political participation indicated that, as predicted, informational uses were more correlated to civic and political action than to recreational uses.


Reduced expression of DKK3 is associated with adverse clinical outcomes of uterine cervical squamous cell carcinoma.
The aim of this study was to assess the expression of DKK3 protein and its target, beta-catenin, in uterine cervical squamous cell carcinoma and to determine potential clinical correlations. Six carcinoma in-situ (CIS) tissues and 88 invasive cervical cancer tissues were included in the study. Twenty-two normal cervical tissues and one gastric cancer tissue were used as controls. The expression of DKK3 and beta-catenin proteins was evaluated by immunohistochemical analysis. Clinical and pathological parameters were obtained from medical records. Survival data were estimated using Kaplan-Meier estimates and compared with a log-rank test. Multivariate analysis was performed using the Cox regression method. DKK3 was predominantly present in the cytoplasm. Beta-catenin was observed only on the cellular membrane of both normal and cancer cells in contrast to earlier reports, in which beta-catenin was localized to the cytoplasm and nucleus of cancer cells. The expressions of beta-catenin and DKK3 were not correlated. Three of 6 CIS (50%) and 57 of 88 invasive cancer specimens (64.8%) had lower DKK3 expression than normal controls. DKK3 expression was decreased in a stage-dependent manner (P = 0.021). The patients with low expression of DKK3 were older than those with high expression of DKK3 (P < 0.01). Moreover, the patients with low DKK3 expression had a significantly lower 5-year disease-free survival rate than those with high DKK3 expression (P = 0.026). A multivariate analysis showed that International Federation of Gynecology and Obstetrics clinical stage and parametrial involvement were independent prognostic factors. Decreased DKK3 expression was associated with advanced International Federation of Gynecology and Obstetrics clinical stages and was predictive of lower disease-free survival in patients with cervical squamous cell carcinoma. DKK3 may be implicated in cervical carcinogenesis through a beta-catenin-independent mechanism.


Case report: postconcussion syndrome after minor head injury.
A 31-yr-old flight medic struck the top of his head while loading a patient onto an ambulance. He sustained a momentary alteration of sensorium but otherwise seemed fine. Approximately 1 week after the incident, he experienced the onset of headaches and disabling vertigo that persisted over the next 2 mo, gradually decreasing in severity with time. Although not deemed significant at the time of injury, a mild head injury can result in postconcussion syndrome, a collection of neurologic symptoms that can persist for some time before resolving. This case emphasizes the need for a period of observation after head trauma before clearing aviators for flying duties.


A review of neosporosis and pathologic findings of Neospora caninum infection in wildlife.
Neospora caninum is an apicomplexan parasite that is the etiologic agent of neosporosis, a devastating infectious disease regarded as a major cause of reproductive loss in cattle and neuromuscular disease in dogs worldwide. This protozoan pathogen is maintained in the environment by a heteroxenous life cycle that involves a definitive canid host and a wide range of intermediate hosts. In recent years, a number of wildlife species have been investigated for their possible involvement in the N. caninum life cycle and many have been implicated as intermediate hosts. However, in many instances these studies have utilized serological and molecular techniques to detect infection in clinically normal animals, and investigation of possible associated morbidity, mortality, and pathology has been neglected. As such, the occurrence and importance of Neospora-associated disease in wildlife species are unknown. In order to improve our understanding of the significance of N. caninum infection in nondomestic species, the present review provides an up-to-date summary of clinical neosporosis and N. caninum-associated pathologic lesions in naturally and experimentally infected wildlife species. We provide a list of all free-ranging and captive wildlife species identified with N. caninum infection to date using currently available diagnostic tools. The advantages and disadvantages of diagnostic methods in wildlife are addressed in order to recommend optimal diagnosis of confirming N. caninum infection and neosporosis in nondomestic species. Although current data would suggest that N. caninum infection does not adversely impact wildlife populations, there is a need for greater international uniformity in the diagnosis of N. caninum infection and neosporosis in nondomestic species in order to assess the true consequences of parasite infection.


Nitrogen deposition, competition and the decline of a regionally threatened legume, Desmodium cuspidatum.
Increased nitrogen (N) deposition, resulting from the combustion of fossil fuels, production of synthetic fertilizers, growth of N(2)-fixing crops and high-intensity agriculture, is one of the anthropogenic factors most likely to cause global biodiversity changes over the next century. This influence may be especially large in temperate zone forests, which are highly N limited and occur in regions with the highest levels of N deposition. Within these ecosystems, N(2)-fixing plants, including legumes, may be more sensitive to N deposition than other plant species. Though it has long been recognized that the competitive edge conferred by N(2)-fixation diminishes with increasing soil N availability, the conservation implications of increased N deposition on native N(2)-fixers have received less attention. We focus on Desmodium cuspidatum, which has experienced dramatic population losses in the last 30-40 years in the northeastern United States. We explore competition between this regionally threatened legume and a common non-N(2)-fixing neighbor, Solidago canadensis, across a gradient of N deposition. Our data show that increased N deposition may be detrimental to N(2)-fixers such as D. cuspidatum in two ways: (1) biomass accumulation in the non-N(2)-fixer, S. canadensis, responds more strongly to increasing N deposition, and (2) S. canadensis competes strongly for available mineral nitrogen and can assimilate N previously fixed by D. cuspidatum, resulting in D. cuspidatum relying more heavily on energetically expensive N(2)-fixation when grown with S. canadensis. N deposition may thus reduce or eliminate the competitive advantage of N(2)-fixing species growing in N-limited ecosystems.


Enhancing Photorealism Enhancement.
We present an approach to enhancing the realism of synthetic images. The images are enhanced by a convolutional network that leverages intermediate representations produced by conventional rendering pipelines. The network is trained via a novel adversarial objective, which provides strong supervision at multiple perceptual levels. We analyze scene layout distributions in commonly used datasets and find that they differ in important ways. We hypothesize that this is one of the causes of strong artifacts that can be observed in the results of many prior methods. To address this we propose a new strategy for sampling image patches during training. We also introduce multiple architectural improvements in the deep network modules used for photorealism enhancement. We confirm the benefits of our contributions in controlled experiments and report substantial gains in stability and realism in comparison to recent image-to-image translation methods and a variety of other baselines.


Malignant peritoneal mesothelioma.
This paper summarizes the author's thoughts about the use of cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy (CS-IPHC) for treatment of peritoneal malignant mesothelioma. Pleural malignant mesotheliomas are by far more common (about ten- to thirty-fold) than the peritoneal variants (2.2 cases per 1 million in the US). Other locations (pericardium, tunica vaginalis) are very rare. It is well known that chemotherapy for mesothelioma is largely unsatisfactory, and measurement of treatment responses can be difficult. Single agent responses are all less than 20% with currently available agents for systemically administered drugs. Multiple drug combinations are typically more toxic, and have yielded little consistent demonstrable benefit with major studies reporting median survivals consistently under a year. There is currently more attention being paid to the response category of "stable" or absence of disease progression in concert with quality of life measurements; all regimens show poor durability. With peritoneal malignant mesothelioma, malignant ascites is a common presentation and a major factor in disease-related morbidity and mortality. Interperitoneal administration of agents is attractive, but drug distribution is an issue, as are response rates and durability. Multiple treatments are required; further, all neoplasms with peritoneal dissemination are typically understaged by current radiologic tests (CT, MRI), and the variable uptake of sugar by the small bowel limits the use of positron-emission tomography (PET) imaging for peritoneal malignant mesothelioma. Also, symptoms of bowel obstruction are not uncommon, and any mechanical component of obstruction will not improve with any form of chemotherapy. The author's approach relies on surgery to achieve the following: 1) accurate staging; 2) tumor debulking, as possible, and treatment of mechanical obstruction as well as prevention of impending obstruction by resection or bypass; and 3) preparation for the use of intra-operative hyperthermic chemotherapy perfusion. This approach has been associated with rapid clinical symptom improvement, as well as a reliable and durable resolution of ascites with a single therapy. Morbidity and mortality have been acceptable with about 27-month median survival. The inability to provide effective systemic therapy to maintain or consolidate these gains is problematic.


A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.
Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.


Informal social support and older persons' psychological well-being in Hong Kong.
This paper focuses on the importance and the effectiveness of various types of informal support for older persons' psychological well-being. It examines the effects of objective measures of informal support (such as size of social networks and frequency of contact) and subjective measures (such as satisfaction with the support received) on psychological well-being of older occupants in different household circumstances (i.e.,living alone, with spouse or relatives, in old urban areas or new towns, in private or public housing). Data were collected from face-to-face interviews with a sample of 518 older persons (224 males, 294 females) aged 60 and over, systematically drawn from a GIS-derived framework of housing districts in old urban areas and new towns in Hong Kong. The results show that both objective and subjective measures of informal support were related to older persons' psychological well-being, but subjective measures of informal support (specifically satisfaction with support received from family members) were found to be more important predictors of psychological well-being. Furthermore, the effects of size of social network on psychological well-being were stronger for older persons who lived alone than for those who lived with a spouse or relatives. The results also show that persons who lived in the old urban areas received more support than did their counterparts in the new towns and older persons who lived in public housing received more objective informal support than those who lived in private housing. The implications of the findings for policy towards older persons in Hong Kong and similar Asia-Pacific societies are discussed.


A Rapid, Sensitive Assay for Ralstonia solanacearum Race 3 Biovar 2 in Plant and Soil Samples Using Magnetic Beads and Real-Time PCR.
The Ralstonia solanacearum species complex causes economically significant diseases in many plant families worldwide. Although generally limited to the tropics and subtropics, strains designated race 3 biovar 2 (R3Bv2) cause disease in cooler tropical highlands and temperate regions. R3Bv2 has not become established in North America but, due to concerns that it could devastate the U.S. potato industry, it has been designated a Select Agent, and is subject to strict quarantine regulations. Quarantine screening for R3Bv2 requires rapid and robust assays applicable to small populations present in plant tissues or soil, and must distinguish R3Bv2 from the multiple other R. solanacearum subgroups. We developed a 100%-accurate real-time polymerase chain reaction (RT-PCR) assay that can detect R3Bv2 populations >1,000 cells ml-1. However, detection by RT-PCR was inhibited by compounds present in some plant and soil samples. Therefore, we developed simple immunomagnetic separation (IMS) and magnetic capture hybridization (MCH) methods to purify R. solanacearum cells or DNA from PCR inhibitors. When coupled with RT-PCR, these tools permitted detection of R3Bv2 at levels >500 cells ml-1 in stem, tuber, and soil samples when direct RT-PCR failed, and reduced detection time from days to hours. IMS-RT-PCR was usually more sensitive than MCH-RT-PCR, especially at lower population levels.


Organometallic acetylides of Pt(II), Au(I) and Hg(II) as new generation optical power limiting materials.
Within the scope of nonlinear optics, optical power limiting (OPL) materials are commonly regarded as an important class of compounds which can protect the delicate optical sensors or human eyes from sudden exposure to damaging intense laser beams. Recent efforts have been devoted to developing organometallic acetylide complexes, dendrimers and polymers as high performance OPL materials of the next generation which can favorably optimize the optical limiting/transparency trade-off issue. These metallated materials offer a new avenue towards a new family of highly transparent homo- and heterometallic optical limiters with good solution processability which outperform those of current state-of-the-art visible-light-absorbing competitors such as fullerenes, metalloporphyrins and metallophthalocyanines. This critical review aims to provide a detailed account on the recent advances of these novel OPL chromophores. Their OPL activity was shown to depend strongly on the electronic characters of the aryleneethynylene ligand and transition metal moieties as well as the conjugation chain length of the compounds. Strategies including copolymerization with other transition metals, change of structural geometry, use of a dendritic platform and variation of the type and content of transition metal ions would strongly govern their photophysical behavior and improve the resulting OPL responses. Special emphasis is placed on the structure-OPL response relationships of these organometallic acetylide materials. The research endeavors for realizing practical OPL devices based on these materials have also been presented. This article concludes with perspectives on the current status of the field, as well as opportunities that lie just beyond its frontier (106 references).


The results after transrectal prostate biopsy with 12 biopsy cores taken.
This report describes the clinical value of transrectal prostate biopsy during which 12 biopsy cores are taken in comparison to the classical sextant method. There were 106 patients included in the study, who had transrectal prostate biopsy (TRB) due to abnormal finding after digitorectal examination (DRE) and/or values of PSA > 4 ng/ml in the period from 4 October 2001 till 14 August 2002. There were 117 biopsies with 12 biopsy cores taken, 6 cores from each lobe. Prostate cancer was confirmed in 49 patients (46%). Out of total number of confirmed cancer cases, initial biopsy detected 94%. There were three patients who had suspicious DRE finding, with PSA value of < 4 ng/ml, but cancer was not detected in any of them. In the patient group with PSA value between 4-10 ng/ml, cancer was detected in 26% of them and in the group with PSA value > 10 ng/ml cancer was detected in 58%. The most common Gleason score in the case of cancer was 7 (43%). During the biopsy procedure, 3 patients experienced strong vasovagal reactions, meaning that out of 117 biopsies incidence of complications was 2.6%. Few days after the biopsy, two patients developed urogenital tract infections (1.7%) and right after the procedure, there was one case of strong hematuria (0.8%) and strong rectal bleeding (0,8%) that needed hospitalization. Our results regarding the incidence of complications do not differ much from the results in the literature. According to data in the literature regarding sextant biopsy, 15-34% of cancer cases remain undiagnosed at initial biopsy. The method of 12 biopsy cores fails to diagnose only 6% of all cancers, but it is important to note that in the mentioned period, re-biopsy was indicated only in 11 from 60 patients with negative biopsies.


Relations between Temperament and Anger Regulation over Early Childhood.
Theory suggests temperamental reactivity [negative affectivity (NA)] and regulation [effortful control (EC)] predict variation in the development of emotion regulation (ER). However, few studies report such relations, particularly studies utilizing observational measures of children's ER behaviors in longitudinal designs. Using multilevel modeling, the present study tested whether (1) between-person differences in mean levels of mother-reported child NA and EC (aggregated across age) and (2) within-person changes in NA and EC from the ages of 18 to 42 months predicted subsequent improvements in laboratory-based observations of children's anger regulation from the ages of 24 to 48 months. As expected, mean level of EC (aggregated across age) predicted longer latency to anger; however, no other temperament variables predicted anger expression. Mean level of EC also predicted the latency to a child's use of one regulatory strategy, distraction. Finally, decreases in NA were associated with age-related changes in how long children used distractions and how quickly they bid calmly to their mother. Implications for relations between temperament and anger regulation are discussed in terms of both conceptual and methodological issues.


Preseptal Cellulitis Or Orbital Cellulitis?
Preseptal cellulitis and orbital cellulitis can both present with increasing swelling, tenderness and redness around the eye, but their management differs. Preseptal cellulitis is more common and much less aggressive than orbital cellulitis. In contrast, orbital cellulitis is a medical emergency requiring urgent management. In this article, we provide a systematic approach to distinguish between preseptal cellulitis and orbital cellulitis at presentation, as the distinction between the two entities and the prompt recognition of orbital cellulitis can be potentially life-saving.


Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma.
Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes. Due to the synthetic complexity of the compound, as well as the low yield from the producing organism, analogs are sought to create synthetically accessible alternatives. As a T-cell lymphoma drug, romidepsin offers a valuable new treatment for diseases with few effective therapies.


Pemphigus vulgaris in a Welsh pony stallion: case report and demonstration of antidesmoglein autoantibodies.
To describe the clinical, histological and immunological findings of an equine case of pemphigus vulgaris, including the demonstration of antidesmoglein (anti-Dsg) autoantibodies. The diagnosis of pemphigus vulgaris was confirmed in a 9-year-old Welsh pony stallion with both direct and indirect immunofluorescence and immunoprecipitation studies, the latter identifying circulating anti-Dsg3 IgG. Treatment with immunosuppressive medications was initiated. Lesions were seen in the perineal area, sheath, mane, tail, eyelids, coronary bands and mucosa of the mouth and oesophagus. Initial corticosteroid treatment improved the clinical signs, but the onset of laminitis necessitated a reduction in dosage, which was associated with a recurrence of lesions and development of oral ulcers. A corneal ulcer developed after 60 days of treatment. Despite treatment with azathioprine, gold salts and dapsone, the disease progressed and the pony was euthanized. Postmortem examination showed additional lesions of the cardia of the stomach. Pemphigus vulgaris is rarely diagnosed in equids. We describe a case that was substantiated by the demonstration of anti-Dsg3 IgG. Response to treatment was poor, with the best response to high doses of prednisolone. Equine pemphigus vulgaris is likely to carry a poor prognosis and if there is no response to treatment, humane euthanasia is warranted.


In vitro functional and immunomodulatory properties of the Lactobacillus helveticus MIMLh5-Streptococcus salivarius ST3 association that are relevant to the development of a pharyngeal probiotic product.
The use of proper bacterial strains as probiotics for the pharyngeal mucosa is a potential prophylactic strategy for upper respiratory tract infections. In this context, we characterized in vitro the functional and immunomodulatory properties of the strains Lactobacillus helveticus MIMLh5 and Streptococcus salivarius ST3 that were selected during previous investigations as promising pharyngeal probiotics. In this study, we demonstrated in vitro that strains MIMLh5 and ST3, alone and in combination, can efficiently adhere to pharyngeal epithelial cells, antagonize Streptococcus pyogenes, and modulate host innate immunity by inducing potentially protective effects. In particular, we found that the strains MIMLh5 and ST3 activate U937 human macrophages by significantly inducing the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α). Nonetheless, the induction of the anti-inflammatory interleukin-10 (IL-10) by MIMLh5 or ST3 was never lower than that of TNF-α, suggesting that these bacteria can potentially exert a regulatory rather than a proinflammatory effect. We also found that the strains MIMLh5 and ST3 induce cyclooxygenase 2 (COX-2) expression and demonstrated that toll-like receptor 2 (TLR-2) participates in the recognition of the strains MIMLh5 and ST3 by U937 cells. Finally, we observed that these microorganisms grow efficiently when cocultured in milk, suggesting that the preparation of a milk-based fermented product containing both MIMLh5 and ST3 can be a practical solution for the administration of these bacteria. In conclusion, we propose the combined use of L. helveticus MIMLh5 and S. salivarius ST3 for the preparation of novel products that display probiotic properties for the pharyngeal mucosa.


Amplified fluorescence emission of bolaamphiphilic perylene-azacrown ether derivatives directed towards molecular recognition events.
Long-term creative approaches have been considered in the design of molecular probes to overcome the quenching effect of important dyes in an aqueous medium. Using the rational donor-acceptor based design principle, we demonstrate herein the different fluorescence states of a non-conjugated symmetrical perylene-azacrown ether system in a solution, from the molecular to the aggregated states. The ethylene-spacer is exceptionally capable of fluorescence enhancement, even in the aggregated state (organic nanoparticle, ONPs, 44 nm), overcoming the quenching effect on changing the solvent from tetrahydrofuran to water. The ONPs with crown ether receptors at the surface show colloidal stability in an aqueous solution. Furthermore, an improved fluorescent state is developed via ONPs-polymer (protamine, Pro) hybridization. Supramolecular interactions between the crown ring and the guanidinium group in Pro play an important role in the ONPs-Pro hybrid formation. The decorated fluorescent hybrid state is finally used as a nano-probe for sensing heparin via the turn-OFF mechanism. The decoration method is further generalized by recognition of the nucleotides. Herein, we detail the bottom-up approach to the molecular design and development of the different fluorescent states of a useful probe. Most excitingly, this new approach is very general and adaptive to facile detection.


Bimolecular recombination in methylammonium lead triiodide perovskite is an inverse absorption process.
Photovoltaic devices based on metal halide perovskites are rapidly improving in efficiency. Once the Shockley-Queisser limit is reached, charge-carrier extraction will be limited only by radiative bimolecular recombination of electrons with holes. Yet, this fundamental process, and its link with material stoichiometry, is still poorly understood. Here we show that bimolecular charge-carrier recombination in methylammonium lead triiodide perovskite can be fully explained as the inverse process of absorption. By correctly accounting for contributions to the absorption from excitons and electron-hole continuum states, we are able to utilise the van Roosbroeck-Shockley relation to determine bimolecular recombination rate constants from absorption spectra. We show that the sharpening of photon, electron and hole distribution functions significantly enhances bimolecular charge recombination as the temperature is lowered, mirroring trends in transient spectroscopy. Our findings provide vital understanding of band-to-band recombination processes in this hybrid perovskite, which comprise direct, fully radiative transitions between thermalized electrons and holes.


A potential bias in safety evaluation during open-label extensions of randomized clinical trials.
To describe a bias that can occur in the analysis of data from certain randomized trials. Although randomized trials are effective at preventing confounding, a potentially strong confounding can arise in certain therapeutic drug trials in which follow-up is extended in an open-label phase that allows switching treatments. Many trials implement eligibility screening that excludes those at high risk of morbidity and mortality. In these trials, disease rates and death rates for the study population can rise rapidly during follow-up as the effect of screening wanes. During the open-label follow-up, a preponderance of patients may switch to the new therapy. If so, then any evaluation of the new therapy that includes follow-up from the open-label phase, as is often the case for safety evaluations, will be confounded. The confounding arises because the person-time experience of those on the new treatment will be more heavily weighted with the open-label phase experience, during which morbidity and mortality rates may be much greater than in the initial phase of follow-up. This confounding may be strong and will be in the direction of making the new treatment look worse, provided that the net switching is toward the new treatment during the open-label phase. The confounding described here is not prevented by randomization because it develops in a non-randomized add-on analysis to the trial. The bias can be removed, however, by controlling for time since randomization in the analysis of the data.


Scale-free channeling patterns near the onset of erosion of sheared granular beds.
Erosion shapes our landscape and occurs when a sufficient shear stress is exerted by a fluid on a sedimented layer. What controls erosion at a microscopic level remains debated, especially near the threshold forcing where it stops. Here we study, experimentally, the collective dynamics of the moving particles, using a setup where the system spontaneously evolves toward the erosion onset. We find that the spatial organization of the erosion flux is heterogeneous in space and occurs along channels of local flux σ whose distribution displays scaling near threshold and follows [Formula: see text], where J is the mean erosion flux. Channels are strongly correlated in the direction of forcing but not in the transverse direction. We show that these results quantitatively agree with a model where the dynamics is governed by the competition of disorder (which channels mobile particles) and particle interactions (which reduces channeling). These observations support that, for laminar flows, erosion is a dynamical phase transition that shares similarity with the plastic depinning transition occurring in dirty superconductors. The methodology we introduce here could be applied to probe these systems as well.


Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer's disease.
Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.


Genetic analyses of live weight and carcass composition traits in purebred Texel, Suffolk and Charollais lambs.
Lamb live weight is one of the key drivers of profitability on sheep farms. Previous studies in Ireland have estimated genetic parameters for live weight and carcass composition traits using a multi-breed population rather than on an individual breed basis. The objective of the present study was to undertake genetic analyses of three lamb live weight and two carcass composition traits pertaining to purebred Texel, Suffolk and Charollais lambs born in the Republic of Ireland between 2010 and 2017, inclusive. Traits (with lamb age range in parenthesis) considered in the analyses were: pre-weaning weight (20 to 65 days), weaning weight (66 to 120 days), post-weaning weight (121 to 180 days), muscle depth (121 to 180 days) and fat depth (121 to 180 days). After data edits, 137 402 records from 50 372 lambs across 416 flocks were analysed. Variance components were derived using animal linear mixed models separately for each breed. Fixed effects included for all traits were contemporary group, age at first lambing of the dam, parity of the dam, a gender by age of the lamb interaction and a birth type by rearing type of the lamb interaction. Random effects investigated in the pre-weaning and weaning weight analyses included animal direct additive genetic, dam maternal genetic, litter common environment, dam permanent environment and residual variances. The model of analysis for post-weaning, muscle and fat depth included an animal direct additive genetic and litter common environment effect only. Significant direct additive genetic variation existed in all cases. Direct heritability for pre-weaning weight ranged from 0.14 to 0.30 across the three breeds. Weaning weight had a direct heritability ranging from 0.17 to 0.27 and post-weaning weight had a direct heritability ranging from 0.15 to 0.27. Muscle and fat depth heritability estimates ranged from 0.21 to 0.31 and 0.15 to 0.20, respectively. Positive direct correlations were evident for all traits. Results revealed ample genetic variation among animals for the studied traits and significant differences between breeds to suggest that genetic evaluations could be conducted on a per-breed basis.


A polyvalent hybrid protein elicits antibodies against the diverse allelic types of block 2 in Plasmodium falciparum merozoite surface protein 1.
Merozoite surface protein 1 (MSP1) of Plasmodium falciparum has been implicated as an important target of acquired immunity, and candidate components for a vaccine include polymorphic epitopes in the N-terminal polymorphic block 2 region. We designed a polyvalent hybrid recombinant protein incorporating sequences of the three major allelic types of block 2 together with a composite repeat sequence of one of the types and N-terminal flanking T cell epitopes, and compared this with a series of recombinant proteins containing modular sub-components and similarly expressed in Escherichia coli. Immunogenicity of the full polyvalent hybrid protein was tested in both mice and rabbits, and comparative immunogenicity studies of the sub-component modules were performed in mice. The full hybrid protein induced high titre antibodies against each of the major block 2 allelic types expressed as separate recombinant proteins and against a wide range of allelic types naturally expressed by a panel of diverse P. falciparum isolates, while the sub-component modules had partial antigenic coverage as expected. This encourages further development and evaluation of the full MSP1 block 2 polyvalent hybrid protein as a candidate blood-stage component of a malaria vaccine.


Endogenous Endophthalmitis Following Streptococcus pneumoniae Meningitis.
A 67-year-old man was transported to our hospital and diagnosed with pneumococcal meningitis. We immediately administered ceftriaxone and vancomycin according to the guidelines, but did not administer dexamethasone to him because he had been previously administered antibiotics. His left eye became complicated by endogenous endophthalmitis on the next day, which resulted in blindness, although his meningitis rapidly ameliorated. In comparison to other patients who have been reported to recover from complications with endophthalmitis after the combination therapy of antibiotics, corticosteroids and vitreous surgery, we consider that this patient's poor visual outcome may have been caused by severe inflammation or the breakdown of the blood ocular barrier due to the action of S. pneumoniae. Corticosteroids may be able to successfully treat such inflammation or disruption of the blood ocular barrier.


A TNF region haplotype offers protection from typhoid fever in Vietnamese patients.
The genomic region surrounding the TNF locus on human chromosome 6 has previously been associated with typhoid fever in Vietnam (Dunstan et al. in J Infect Dis 183:261-268, 2001). We used a haplotypic approach to understand this association further. Eighty single nucleotide polymorphisms (SNPs) spanning a 150 kb region were genotyped in 95 Vietnamese individuals (typhoid case/mother/father trios). A subset of data from 33 SNPs with a minor allele frequency of >4.3% was used to construct haplotypes. Fifteen SNPs, which tagged the 42 constructed haplotypes were selected. The haplotype tagging SNPs (T1-T15) were genotyped in 380 confirmed typhoid cases and 380 Vietnamese ethnically matched controls. Allelic frequencies of seven SNPs (T1, T2, T3, T5, T6, T7, T8) were significantly different between typhoid cases and controls. Logistic regression results support the hypothesis that there is just one signal associated with disease at this locus. Haplotype-based analysis of the tag SNPs provided positive evidence of association with typhoid (posterior probability 0.821). The analysis highlighted a low-risk cluster of haplotypes that each carry the minor allele of T1 or T7, but not both, and otherwise carry the combination of alleles *12122*1111 at T1-T11, further supporting the one associated signal hypothesis. Finally, individuals that carry the typhoid fever protective haplotype *12122*1111 also produce a relatively low TNF-alpha response to LPS.


Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.
Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. Published literature. All persons with newly diagnosed colorectal cancer and their relatives. Lifetime. Third-party payer. Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained. The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years. Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered. Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome. National Institutes of Health.


Long-term follow-up of autologous stem cell transplantation after intensive chemotherapy in patients with myelodysplastic syndrome or secondary acute myeloid leukemia.
We report on the outcomes of 53 patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia secondary to MDS, autografted in first complete remission. Five (9.4%) died from the procedure whereas hematological reconstitution occurred in all the remaining patients. Forty patients (75%) relapsed, with 87.5% of the relapses occurring within 2 years of the autologous transplant. With a median follow-up of 6.2 years, the median actuarial disease-free survival and overall survival were 8 and 17 months after autograft, respectively. Karyotype was the only prognostic factor for disease-free and overall survival. The eight survivors (15%), including two patients with unfavorable or intermediate karyotype, remained in first complete remission 50+ to 119+ months after transplantation and are probably cured.


Brain abscess at the Kenyatta Nationai, Hospital, Nairobi.
To study the aetiology, mode of presentation and outcome following treatment of brain abscesses at the Kenyatta National Hospital, Nairobi. A retrospective study. Kenyatta National Hospital, Nairobi. Sixty five patients with brain abscesses who were seen at Kenyatta National Hospital between January 1989 and December 1993. Twenty patients died following surgery (30.7% mortality). Eight per cent of the patients who underwent surgery were serologically positive for the human immune deficiency virus (HIV). When these patients were excluded mortality was 25%. There were more male patients than females (ratio 2.4:1). Thirty eight per cent of the patients were children below the age of ten years. Trauma was the commonest cause of brain abscess. The aetiology was unknown in 24% of the cases. Twenty six patients who were HIV positive and had suspected brain abscesses were not included in this study because they did not undergo surgery. The commonest organisms isolated were Staphylococci, Streptococci, Klebsiella and Haemophylus influenzae. Sixty eight per cent of the patients had seizures. All the patients were diagnosed by computerised tomography (CT) scanning of the brain. Surgical treatment was by multiple burr hole aspirations and excision through craniotomy. Brain abscess is still a major cause of morbidity at the Kenyatta National Hospital with a high overall mortality of 30.7% during the period under study.


Predicting cryptic links in host-parasite networks.
Networks are a way to represent interactions among one (e.g., social networks) or more (e.g., plant-pollinator networks) classes of nodes. The ability to predict likely, but unobserved, interactions has generated a great deal of interest, and is sometimes referred to as the link prediction problem. However, most studies of link prediction have focused on social networks, and have assumed a completely censused network. In biological networks, it is unlikely that all interactions are censused, and ignoring incomplete detection of interactions may lead to biased or incorrect conclusions. Previous attempts to predict network interactions have relied on known properties of network structure, making the approach sensitive to observation errors. This is an obvious shortcoming, as networks are dynamic, and sometimes not well sampled, leading to incomplete detection of links. Here, we develop an algorithm to predict missing links based on conditional probability estimation and associated, node-level features. We validate this algorithm on simulated data, and then apply it to a desert small mammal host-parasite network. Our approach achieves high accuracy on simulated and observed data, providing a simple method to accurately predict missing links in networks without relying on prior knowledge about network structure.


Estimated societal costs of stroke in the UK based on a discrete event simulation.
there are around 100,000 new stroke cases and over a million people living with its consequences annually in the UK. This has large impacts on health and social care, unpaid carers and lost productivity. We aimed to estimate associated costs. we estimated 2014/2015 annual mean cost per person and aggregate UK cost of stroke for individuals aged ≥40 from a societal perspective. Health and social care costs in the first and subsequent years after stroke were estimated from discrete event simulation modelling, with probability of progression and length of receipt of different health and social care services obtained from routine registry and audit data. Unpaid care hours and lost productivity were obtained from trial data. UK unit costs were applied to estimate mean costs. Epidemiological estimates of stroke incidence and prevalence were then applied to estimate aggregate costs for the UK. mean cost of new-onset stroke is £45,409 (95% CI 42,054-48,763) in the first year after stroke and £24,778 (20,234-29,322) in subsequent years. Aggregate societal cost of stroke is £26 billion per year, including £8.6 billion for NHS and social care. The largest component of total cost was unpaid care (61%) and, given high survival, £20.6 billion related to ongoing care. the estimated aggregate cost of stroke substantially exceeds previous UK estimates. Since most of the cost is attributed to unpaid care, interventions aimed at rehabilitation and reducing new and recurrent stroke are likely to yield substantial benefits to carers and cost savings to society.