Visual appearance of the virtual hand affects embodiment in the virtual hand illusion.
Body ownership (the feeling that one's body belongs to oneself) is commonly studied with Rubber hand illusion (RHI) paradigm that allows inducing a temporary illusory feeling of ownership of a life-sized rubber hand. However, it remains unclear whether illusory ownership of the fake hand relies on the same mechanisms as ownership of one's own real hand. Here, we directly compared ownership of the own hand (OH) and fake hand (FH) in the same set of conditions within immersive virtual reality. We obtained behavioral (proprioceptive drift) and subjective (questionnaire) measures of ownership and disownership for virtual OH, FH and object (Obj) that were located congruently or incongruently with the participant's real hand and were stimulated synchronously or asynchronously with the real hand. Both OH and FH (but not Obj) were embodied after synchronous stimulation in both locations. Crucially, subjective ownership of the OH was stronger than of the FH in congruent location after synchronous stimulation. It was also present after asynchronous stimulation, being stronger when the virtual OH was subjectively more similar to the real hand. The results suggest that the detailed appearance of the body might act as an additional component in the construction of body ownership.


Postoperative intensity modulated radiation therapy in high risk prostate cancer: a dosimetric comparison.
The aim of this study was to compare intensity-modulated radiation therapy (IMRT) with 3D conformal technique (3D-CRT), with respect to target coverage and irradiation of organs at risk for high dose postoperative radiotherapy (PORT) of the prostate fossa. 3D-CRT and IMRT treatment plans were compared with respect to dose to the rectum and bladder. The dosimetric comparison was carried out in 15 patients considering 2 different scenarios: (1) exclusive prostate fossa irradiation, and (2) pelvic node irradiation followed by a boost on the prostate fossa. In scenario (1), a 3D-CRT plan (box technique) and an IMRT plan were calculated and compared for each patient. In scenario (2), 3 treatment plans were calculated and compared for each patient: (a) 3D-CRT box technique for both pelvic (prophylactic nodal irradiation) and prostate fossa irradiation (3D-CRT only); (b) 3D-CRT box technique for pelvic irradiation followed by an IMRT boost to the prostatic fossa (hybrid 3D-CRT and IMRT); and (c) IMRT for both pelvic and prostate fossa irradiation (IMRT only). For exclusive prostate fossa irradiation, IMRT significantly reduced the dose to the rectum (lower Dmean, V50%, V75%, V90%, V100%, EUD, and NTCP) and the bladder (lower Dmean, V50%, V90%, EUD and NTCP). When prophylactic irradiation of the pelvis was also considered, plan C (IMRT only) performed better than plan B (hybrid 3D-CRT and IMRT) as respect to both rectum and bladder irradiation (reduction of Dmean, V50%, V75%, V90%, equivalent uniform dose [EUD], and normal tissue complication probability [NTCP]). Plan (b) (hybrid 3D-CRT and IMRT) performed better than plan (a) (3D-CRT only) with respect to dose to the rectum (lower Dmean, V75%, V90%, V100%, EUD, and NTCP) and the bladder (Dmean, EUD, and NTCP). Postoperative IMRT in prostate cancer significantly reduces rectum and bladder irradiation compared with 3D-CRT.


Endothelial angiogenic activity and adipose angiogenesis is controlled by extracellular matrix protein TGFBI.
Several studies have suggested that extracellular matrix (ECM) remodeling and the microenvironment are tightly associated with adipogenesis and adipose angiogenesis. In the present study, we demonstrated that transforming growth factor-beta induced (TGFBI) suppresses angiogenesis stimulated by adipocyte-conditioned medium (Ad-CM), both in vitro and in vivo. TGFBI knockout (KO) mice exhibited increased numbers of blood vessels in adipose tissue, and blood vessels from these mice showed enhanced infiltration into Matrigel containing Ad-CM. The treatment of Ad-CM-stimulated SVEC-10 endothelial cells with TGFBI protein reduced migration and tube-forming activity. TGFBI protein suppressed the activation of the Src and extracellular signaling-related kinase signaling pathways of these SVEC-10 endothelial cells. Our findings indicated that TGFBI inhibited adipose angiogenesis by suppressing the activation of Src and ERK signaling pathways, possibly because of the stimulation of the angiogenic activity of endothelial cells.


Surgical outcomes after epiretinal membrane peeling combined with cataract surgery.
To compare functional and anatomical outcomes after idiopathic epiretinal membrane (ERM) peeling combined with phacoemulsification and intraocular lens implantation versus ERM peeling alone. A retrospective, non-randomised comparative case series study was conducted of 81 eyes from 79 patients who underwent ERM peeling at the Beth Israel Deaconess Medical Center between 2001 and 2010. Eyes that underwent combined surgery for ERM and cataracts (group 1) were compared with those that had ERM peeling alone (group 2) with respect to best-corrected visual acuity at 6 months and 1 year after surgery, postoperative central macular thickness (CMT) as measured on optical coherence tomography, and rates of complications, including elevated intraocular pressure (IOP), ERM recurrence and need for reoperation. Mean logMAR visual acuity improved significantly in both groups at 6 months (p<0.001) and 1 year (p<0.001) after surgery. There was no statistical difference between the two groups in visual acuity improvement at 6 months (p=0.108) or 1 year (p=0.094). Mean CMT of both groups also significantly decreased after surgery (p=0.002), with no statistical difference in CMT reduction between the two groups, but a trend toward less CMT reduction in group 1 (p=0.061). The rates of complications, including IOP elevation, ERM recurrence and frequency of reoperation, were similar in the two groups, with non-statistical trends toward greater ERM recurrence (p=0.084) and need for reoperation (p=0.096) in those that had combined surgery. Combined surgery for ERMs and cataracts may potentially be as effective as membrane peeling alone with respect to visual and anatomical outcomes. Further studies are necessary to determine if there may be greater ERM recurrence or need for reoperation after combined surgery.


Does this patient have myasthenia gravis?
Clinicians must be able to diagnose myasthenia gravis, since delays in establishing the diagnosis may put patients at risk for complications from this treatable disease. To determine if items in the history and examination or results of simple tests change the likelihood of myasthenia gravis as a diagnosis. MEDLINE search of English-language articles (January 1966-January 2005) using the terms myasthenia gravis, diagnosis, and test, and a search of bibliographies of retrieved articles. Studies evaluating a particular symptom or sign in patients both with and without myasthenia gravis. Of 640 articles retrieved, 33 were eligible for review. Of these, 15 met inclusion criteria and form the basis of this review. Two authors independently reviewed each study to determine eligibility, abstracted data using a standardized instrument, and classified study quality using previously published criteria. A history of "speech becoming unintelligible during prolonged speaking" and the presence of the peek sign increase the likelihood of myasthenia gravis (likelihood ratio [LR], 4.5; 95% confidence interval [CI], 1.2-17.0 and LR, 30.0; 95% CI, 3.2-278.0, respectively). Their absence does not significantly reduce the likelihood of myasthenia gravis. The identified studies only assessed 1 other historical feature and sign each ("food remaining in the mouth after swallowing" and quiver eye movements, respectively), and neither of these significantly changes the likelihood of myasthenia. The ice test is useful when the response is abnormal (summary positive LR, 24.0; 95% CI, 8.5-67.0) and diminishes the likelihood of myasthenia gravis when the response is normal (summary negative LR, 0.16; 95% CI, 0.09-0.27). A positive response to an anticholinesterase medication (mainly edrophonium test) increases the probability of a diagnosis of myasthenia gravis (summary positive LR, 15.0; 95% CI, 7.5-31.0), and a negative response reduces the diagnostic probability of myasthenia (summary negative LR, 0.11; 95% CI, 0.06-0.21). An abnormal sleep test result is useful in confirming the diagnosis (LR, 53.0; 95% CI, 3.4-832.0). The rest and sleep tests make the probability of myasthenia unlikely when results are normal (LR, 0.52; 95% CI, 0.29-0.95 and LR, 0.01; 95% CI, 0.00-0.16, respectively). Items in the history and physical examination along with results of certain simple tests performed in the office (ice test, sleep test, and edrophonium test) are useful in predicting the likelihood of myasthenia gravis. These results must be interpreted with caution, however, given the high prevalence of disease in the populations reported in clinical studies. This review is limited by the small number of signs and symptoms scientifically studied and reported in the literature. Future studies evaluating the value of common historical features and easy maneuvers commonly known and practiced by experts in the clinical diagnosis of myasthenia are needed.


The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination.
The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.


Plants and microbes assisted selenium nanoparticles: characterization and application.
Selenium is an essential trace element and is an essential component of many enzymes without which they become inactive. The Se nanoparticles of varying shape and size may be synthesized from Se salts especially selenite and selenates in presence of reducing agents such as proteins, phenols, alcohols and amines. These biomolecules can be used to reduce Se salts in vitro but the byproducts released in the environment may be hazardous to flora and fauna. In this review, therefore, we analysed in depth, the biogenic synthesis of Se nanoparticles, their characterization and transformation into t- Se, m-Se, Se-nanoballs, Se-nanowires and Se-hollow spheres in an innocuous way preventing the environment from pollution. Their shape, size, FTIR, UV-vis, Raman spectra, SEM, TEM images and XRD pattern have been analysed. The weak forces involved in aggregation and transformation of one nano structure into the other have been carefully resolved.


Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes.
To identify selective compounds for nonadrenergic I1-imidazoline receptors (I1), the affinities of 22 ligands for [125I]p-iodoclonidine binding have been compared at human platelet I1-imidazoline binding sites (analyzed under norepinephrine mask of alpha-2 AR) and at human alpha-2A, alpha-2B and alpha-2C adrenoceptors stably expressed on transfected Chinese hamster ovary cells. Competition curves at the platelet I1-imidazoline binding site were biphasic for most compounds. Only tizanidine and BDF,6143 displayed monophasic I1 competition curves. Agmatine, an endogenous neurotransmitter candidate for the I1-imidazoline receptor, was identified as the most selective agent for a subcomponent of platelet I1 sites. The affinity of agmatine at the high affinity component of platelet I1 sites was 1400-fold selective over alpha-2A adrenoceptors, 5000-fold selective over alpha-2B adrenoceptors and 800-fold selective over alpha-2C adrenoceptors. Moxonidine and tizanidine also displayed selectivities for a high affinity component of the platelet I1 binding sites over alpha-2 adrenoceptors. Naphazoline was the most selective compound for the high affinity state of the alpha-2A adrenoceptor, displaying 7-, 23- and 9-fold higher affinity than alpha-2B, alpha-2C and platelet I1-midazoline binding sites, respectively. No single selective compound was identified for the alpha-2B adrenoceptor. Norepinephrine displayed, respectively, 18- and 31-fold selectivity for the high affinity state of the alpha-2C adrenoceptor as compared to alpha-2A- or alpha-2B adrenoceptors, and was > 100,000- fold selective over platelet I1-imidazoline sites. Thus, human alpha-2 adrenoceptors and the platelet I1-imidazoline binding site can be clearly discriminated based on their affinities for certain compounds.


Interferometric investigation and simulation of refractive index in glass matrixes containing nanoparticles of varying sizes.
The relationship between refractive index and nanoparticle radii of cadmium selenide (CdSe) nanoparticles embedded within glass matrixes was investigated experimentally and by simulations. A homemade automated Michelson interferometer arrangement employing a rotating table and a He-Ne laser source at a wavelength of 632.8 nm determined the refractive index versus nanoparticle radii of embedded cadmium selenide (CdSe) nanoparticles. The refractive index was found to decrease linearly with nanoparticle radius increase. However, one sample showed a step increase in refractive index; on spectroscopic analysis, it was found that its resonant wavelength matched that of the He-Ne source wavelength. The simulations showed that two conditions caused the step increase in refractive index: low plasma frequency and matched sample and source resonances. This simple interferometer setup defines a new method of determining the radii of nanoparticles embedded in substrates and enables refractive index tailoring by modification of exact annealing conditions.


Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity.
Rationale: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. Methods: Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. Results: CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. Conclusions: CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.


Roentgen stereophotogrammetric analysis as a predictor of mechanical loosening of knee prostheses.
The tibial components in 143 patients with total knee replacements performed before 1988 were assessed for micromotion using roentgen stereophotogrammetric analysis (RSA) over a period of 13 years. The fixation of the prostheses remained clinically sound in all cases, although revision had been required for other reasons in seven. In a second group taken from all cases with RSA available on our full database to 1990, 15 tibial components had been followed by RSA from the insertion until, 1 to 11 years after the initial arthroplasty, they were revised for mechanical loosening of the tibial component; 12 of these comprised all the loosenings in the base group, thus making a total of 155 consecutive cases, while an additional three were inserted after the base material had been compiled. The mean migration in the first group was about 1 mm at one year, but subsequent migration was slower, reaching a mean of about 1.5 mm after ten years. About one-third migrated continuously throughout follow-up, while two-thirds ceased to migrate after one to two years. In the revision group, 14 components had migrated continuously and at one year significantly more than those in the first group. One revision case lacked the crucial one-year follow-up and could not be classified. These findings suggest that mechanical loosening begins early in the postoperative period. Clinical symptoms which necessitate revision, seen at this stage in 20% of abnormally migrating tibial components, may not appear until up to ten years after the operation.(ABSTRACT TRUNCATED AT 250 WORDS)


Acid-soluble internal capsules for closed-face cassette elemental sampling and analysis of workplace air.
Airborne particles that are collected using closed-face filter cassettes (CFCs), which are used widely in the sampling of workplace aerosols, can deposit in places other than on the filter and thereby may not be included in the ensuing analysis. A technique for ensuring that internal non-filter deposits are included in the analysis is to collect airborne particles within an acid-soluble internal capsule that, following sampling, can be dissolved along with the filter for subsequent elemental analysis. An interlaboratory study (ILS) was carried out to evaluate the use of cellulosic CFC capsule inserts for their suitability in the determination of trace elements in airborne samples. The ILS was performed in accordance with an applicable ASTM International standard practice, ASTM E691, which describes statistical procedures for investigating interlaboratory precision. Performance evaluation materials consisted of prototype cellulose acetate capsules attached to mixed-cellulose ester filters. Batches of capsules were dosed with Pb-containing materials (standard aqueous solutions, and certified reference material soil and paint). Also, aerosol samples containing nine target analyte elements (As, Cd, Co, Cr, Cu, Fe, Pb, Mn, and Ni) were generated using a multiport sampler; various concentrations and sampling times were employed to yield samples fortified at desired loading levels. Triplicates of spiked capsules at three different loadings were conveyed to each volunteer laboratory; loading levels were unknown to the participants. The laboratories were asked to prepare the samples by acid dissolution and to analyze aliquots of extracted samples by atomic spectrometry in accordance with applicable ASTM International Standards. Participants were asked to report their results in units of μg of each target element per sample. For the elements investigated, inter-laboratory precision and recovery estimates from the participating laboratories demonstrated the utility of the cellulosic capsule inserts for the measurement of sampled trace elements.


Mitro-aortic infective endocarditis produced by Erysipelothrix rhusiopathiae: case report and review of the literature.
Endocarditis produced by Erysipelothrix rhusiopathiae is an uncommon disease in humans. This bacterial species is found worldwide as a commensal or a pathogen in many animals. Infection in humans is usually due to occupational exposure. The case is reported of a 43-year-old male parrot breeder with native aortic and mitral valve endocarditis and NYHA class II heart failure at six months after wound infection. The patient was discharged after six weeks' treatment with intravenous penicillin G and replacement of the mitral and aortic valves due to severe regurgitation. At one year after surgery the patient was asymptomatic and infection-free.


Recombinant rabies virus as potential live-viral vaccines for HIV-1.
Recombinant, replication-competent rabies virus (RV) vaccine strain-based vectors were developed expressing HIV type I (HIV-1) envelope glycoprotein (gp160) from both a laboratory-adapted (CXCR4-tropic) and a primary (dual-tropic) HIV-1 isolate. An additional transcription stop/start unit within the RV genome was used to express HIV-1 gp160 in addition to the other RV proteins. The HIV-1 gp160 protein was stably and functionally expressed, as indicated by fusion of human T cell lines after infection with the recombinant RVs. Inoculation of mice with the recombinant RVs expressing HIV-1 gp160 induced a strong humoral response directed against the HIV-1 envelope protein after a single boost with recombinant HIV-1 gp120 protein. Moreover, high neutralization titers up to 1:800 against HIV-1 could be detected in the mouse sera. These data indicate that a live recombinant RV, a rhabdovirus, expressing HIV-1 gp160 may serve as an effective vector for an HIV-1 vaccine.


Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates.
Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90-94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.


Single enzyme electroanalysis.
Traditional studies of enzymatic activity rely on the combined kinetics of millions of enzyme molecules to produce a product, an experimental approach that may wash out heterogeneities that exist between individual enzymes. Evaluating these properties on an enzyme-by-enzyme basis represents an unambiguous means of elucidating heterogeneities; however, the quantification of enzymatic activity at the single-enzyme level is fundamentally limited by the maximum catalytic rate, kcat, inherent to a given enzyme. For electrochemical methods measuring current, single enzymes must turn over greater than 107 molecules per second to produce a measurable signal on the order of 10-12 A. Enzymes with this capability are extremely rare in nature, with typical kcat values for biologically relevant enzymes falling between 1 and 10 000 s-1. Thus, clever amplification strategies are necessary to electrochemically detect the vast majority of enzymes. This review details the progress toward the electroanalytical detection and evaluation of single enzyme kinetics largely focused on the nanoimpact method, a chronoamperometric detection strategy that monitors the change in the current-time profile associated with stochastic collisions of freely diffusing entities (e.g., enzymes) onto a microelectrode or nanoelectrode surface. We discuss the experimental setups and methods developed in the last decade toward the quantification of single molecule enzymatic rates. Special emphasis is given to the limitations of measurement science in the observation of single enzyme activity and feasible methods of signal amplification with reasonable bandwidth.


Mortality among elderly Hispanics in the United States: past evidence and new results.
We used vital records and census data and Medicare and NUMIDENT records to estimate age- and sex-specific death rates for elderly non-Hispanic whites and Hispanics, including five Hispanic subgroups: persons born in Cuba, Mexico, Puerto Rico, other foreign countries, and the United States. We found that corrections for data errors in vital and census records lead to substantial changes in death rates for Hispanics and that conventionally constructed Hispanic death rates are lower than rates based on Medicare-NUMIDENT records. Both sources revealed a Hispanic mortality advantage relative to non-Hispanic whites that holds for most Hispanic subgroups. We also present a new methodology for inferring Hispanic origin from a combination of surname, given name, and county of residence.


Factors affecting transcutaneous bilirubin measurement: effect of daylight.
The purpose of this study was to determine whether daylight might affect the accuracy and reliability of TcB measurement at the forehead and sternum. One hundred and seven full-term newborn infants were divided into two groups. Babies in group I (N = 59) were kept near the window which was sometimes directly exposed to daylight, and babies in group II (N = 48) were kept on the door side of the room which had no direct daylight, during the first week of life. The result indicates that daylight is one of the significant factors affecting TcB measurement at the forehead, contributing to poor correlation between TcB reading at the forehead and serum bilirubin concentrations. We suggest the necessity of obtaining TcB readings at the forehead and sternum, at least, in order to improve the accuracy and reliability of such measurements in infants.


Diabetes related risk factors did not explain the increased risk for urinary incontinence among women with diabetes. The Norwegian HUNT/EPINCONT study.
Previous studies have shown an association between diabetes mellitus (DM) and urinary incontinence (UI) in women, especially severe UI. The purpose of this study was to investigate whether diabetes related variables could explain this association. The study is part of the EPINCONT study, which is based on the large Nord-Trøndelag Health Study 2 (HUNT 2), performed in the county of Nord-Trøndelag, Norway, during the years 1995 - 1997. Questions on diabetes and UI were answered by a total of 21 057 women aged 20 years and older. Of these 685 were identified as having diabetes, and thus comprise the population of our study. A variety of clinical and biochemical variables were recorded from the participants. Blood-glucose, HbA1c, albumine:creatinine ratio (ACR), duration of diabetes, diabetes treatment, type of diabetes, cholesterol and triglycerides did not significantly differ in women with and without UI in crude analyses. However, the diabetic women with UI had more hospitalizations during the last 12 months, more homecare, and a higher prevalence of angina and use of oestrogene treatment (both local and oral/patch). After adjusting for age, BMI, parity and smoking, there were statistically significant associations between any UI and angina (OR 1.89; 95% CI: 1.22 - 2.93), homecare (OR 1.72; 95% CI: 1.02 - 2.89), and hospitalization during the last 12 months (OR 1.67; 95% CI: 1.18 - 2.38). In adjusted analyses severe UI was also significantly associated with the same variables, and also with diabetes drug treatment (OR 2.10; 95% CI: 1.07 - 4.10) and stroke (OR 2.47; 95% CI: 1.09 - 5.59). No single diabetes related risk factor seems to explain the increased risk for UI among women with diabetes. However, we found associations between UI and some clinical correlates of diabetes.


Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2.
Protein kinase D2 (PKD2), a member of the PKD family of serine/threonine kinases, is localized in various subcellular compartments including the nucleus where the kinase accumulates upon activation of G-protein-coupled receptors. We define three critical post-translational modifications required for nuclear accumulation of PKD2 in response to activation of the CCK2 receptor (CCK2R): phosphorylation at Ser706 and Ser710 within the activation loop by PKC eta leading to catalytic activity and phosphorylation at Ser244 within the zinc-finger domain, which is crucial for blocking nuclear export of active PKD2 by preventing its interaction with the Crm-1 export machinery. We identify CK1delta and epsilon as upstream activated kinases by CCK2R that phosphorylate PKD2 at Ser244. Moreover, nuclear accumulation of active PKD2 is a prerequisite for efficient phosphorylation of its nuclear substrate, HDAC7. Only nuclear, active PKD2 mediates CCK2R-induced HDAC7 phosphorylation and Nur77 expression. Thus, we define a novel, compartment-specific signal transduction pathway downstream of CCK2R that phosphorylates PKD2 at three specific sites, results in nuclear accumulation of the active kinase and culminates in efficient phosphorylation of nuclear PKD2 substrates in human gastric cancer cells.


Structured approaches for the screening and diagnosis of childhood tuberculosis in a high prevalence region of South Africa.
To measure agreement between nine structured approaches for diagnosing childhood tuberculosis; to quantify differences in the number of tuberculosis cases diagnosed with the different approaches, and to determine the distribution of cases in different categories of diagnostic certainty. We investigated 1445 children aged < 2 years during a vaccine trial (2001-2006) in a rural South African community. Clinical, radiological and microbiological data were collected prospectively. Tuberculosis case status was determined using each of the nine diagnostic approaches. We calculated differences in case frequency and categorical agreement for binary (tuberculosis/not tuberculosis) outcomes using McNemar's test (with 95% confidence intervals, CIs) and Cohen's kappa coefficient (Kappa). Tuberculosis case frequency ranged from 6.9% to 89.2% (median: 41.7). Significant differences in case frequency (P < 0.05) occurred in 34 of the 36 pair-wise comparisons between structured diagnostic approaches (range of absolute differences: 1.5-82.3%). Kappa ranged from 0.02 to 0.71 (median: 0.18). The two systems that yielded the highest case frequencies (89.2% and 70.0%) showed fair agreement (Kappa: 0.33); the two that yielded the lowest case frequencies (6.9% and 10.0%) showed slight agreement (Kappa: 0.18). There is only slight agreement between structured approaches for the screening and diagnosis of childhood tuberculosis and high variability between them in terms of case yield. Diagnostic systems that yield similarly low case frequencies may be identifying different subpopulations of children. The study findings do not support the routine clinical use of structured approaches for the definitive diagnosis of childhood tuberculosis, although high-yielding systems may be useful screening tools.


Using community health workers to deliver a scalable integrated parenting program in rural China: A cluster-randomized controlled trial.
Inadequate care during early childhood can lead to long-term deficits in skill development. Parenting programs are promising tools for improving parenting practices and opportunities for healthy development. We implemented a non-masked cluster-randomized controlled trial in rural China in order to assess the effectiveness of an integrated home-visitation program that includes both psychosocial stimulation and health promotion at fostering development and health outcomes of infants and toddlers in rural China. All 6-18 month-old children of two rural townships and their main caregiver were enrolled. Villages were stratified by township and randomly assigned to intervention or control. Specifically, in September 2015 we assigned 43 clusters to treatment (21 villages, 222 caregiver-child dyads) or control (22 villages, 227 caregiver-child dyads). In the intervention group, community health workers delivered education and training on how to provide young children with psychosocial stimulation and health care (henceforth psychosocial stimulation and health promotion) during bi-weekly home visits over the period of one year. The control group received no home visits. Primary outcomes include measures of child development (i.e. the Bayley Scales of Infant and Toddler Development, third edition-or Bayley-III) and health (i.e. measures of morbidity, nutrition, and growth). Secondary outcomes are measures of parenting practices. Intention-to-treat (ITT) effects show that the intervention led to an improvement of 0·24 standard deviations (SD) [95% CI 0·04 SD-0·44 SD] in cognitive development and to a reduction of 8·1 [95% CI 3·8-12·4] percentage points in the risk of diarrheal illness. In addition, we find positive effects on parenting practices mirroring these results. We conclude that an integrated psychosocial stimulation and health promotion program improves development and health outcomes of infants and toddlers (6-30 month-old children) in rural China. Because of low incremental costs of adding program components (that is, adding health promotion to psychosocial stimulation programs), integrated programs may be cost-effective.


Topical mitomycin as an adjunct to choanal atresia repair.
To evaluate the use of topical mitomycin in choanal atresia repair to reduce the development of granulation tissue and cicatrix. Retrospective case series in 2 tertiary care centers. Twenty patients with either unilateral or bilateral congenital choanal atresia underwent repair using the transnasal endoscopic approach, the transpalatal approach, or both. The surgeons favor the use of the endoscopic transnasal drillout technique for all unilateral cases of choanal atresia and for selected bilateral cases. We describe our experience and treatment paradigm for these 20 patients (15 with unilateral atresia, 5 with bilateral atresia). Topical application of mitomycin was used, and in some cases postoperative stenting, for a period of 1 to 2 weeks. In 8 cases, a second application of mitomycin was used. Follow-up ranged from 3 months to 2 years (mean, 9 months). The patency of the choanae without respiratory distress or nasal drainage, as assessed by endoscopic evaluation, determined a successful repair. Of the 20 patients, 17 retained patent airways. Three patients experienced improvement from a total atresia to a narrowed, stenotic choana. The use of mitomycin as an adjunct to the surgical repair of choanal atresia may offer improved patency with a decreased need for stenting, dilatations, and revision surgery. Newer endoscopic techniques with powered instrumentation further enhance the safety and efficacy in the repair of choanal atresia.


Exploring the Multifunctional Roles of Odontoglossum Ringspot Virus P126 in Facilitating Cymbidium Mosaic Virus Cell-to-Cell Movement during Mixed Infection.
Synergistic interactions among viruses, hosts and/or transmission vectors during mixed infection can alter viral titers, symptom severity or host range. Viral suppressors of RNA silencing (VSRs) are considered one of such factors contributing to synergistic responses. Odontoglossum ringspot virus (ORSV) and cymbidium mosaic virus (CymMV), which are two of the most significant orchid viruses, exhibit synergistic symptom intensification in Phalaenopsis orchids with unilaterally enhanced CymMV movement by ORSV. In order to reveal the underlying mechanisms, we generated infectious cDNA clones of ORSV and CymMV isolated from Phalaenopsis that exerted similar unilateral synergism in both Phalaenopsis orchid and Nicotiana benthamiana. Moreover, we show that the ORSV replicase P126 is a VSR. Mutagenesis analysis revealed that mutation of the methionine in the carboxyl terminus of ORSV P126 abolished ORSV replication even though some P126 mutants preserved VSR activity, indicating that the VSR function of P126 alone is not sufficient for viral replication. Thus, P126 functions in both ORSV replication and as a VSR. Furthermore, P126 expression enhanced cell-to-cell movement and viral titers of CymMV in infected Phalaenopsis flowers and N. benthamiana leaves. Taking together, both the VSR and protein function of P126 might be prerequisites for unilaterally enhancing CymMV cell-to-cell movement by ORSV.


Klebsiella pneumoniae psoas abscess: predominance in diabetic patients and grave prognosis in gas-forming cases.
Seven cases of psoas abscess caused by Klebsiella pneumoniae were observed at the National Cheng Kung University Hospital within a period of 4.5 years. These cases constituted 25% of a total 28 episodes of non-tuberculous psoas abscess, ranking second to those caused by Staphylococcus aureus (8 cases). Eight cases of psoas abscess caused by K. pneumoniae were identified from Medline, and 5 of which were reported from Taiwan. Of these 8 cases, 1 neonatal case was excluded, and the remaining 7 adult cases were combined with the 7 cases in this series for analysis. The mean age was 53.8 years, and diabetes mellitus was the most common underlying disease. Fever and pain on the flank and back area were the common findings. The interval between the onset of symptoms and diagnosis ranged from 1 to 60 days. The most common sites of concurrent infection were the urinary tract (6 cases; 43%) and bone (3 cases; 21%). All patients received percutaneous or surgical drainage in addition to antibiotic treatment. Gas formation was present in 5 of the 12 patients recorded, and 4 of them died during hospitalization. Only 1 patient had a metastatic infection with osteomyelitis of the left radius and right humerus; he had experienced 5 episodes of recurrent K. pneumoniae infections in different sites. We concluded that K. pneumoniae should be considered as an important endemic pathogen of psoas abscess in diabetics in Taiwan. The high mortality rate in the gas-forming cases should also be highlighted. Early recognition, empiric antimicrobial coverage for K. pneumoniae, and aggressive drainage or debridement are indicated in these patients.


Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity.
Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8+ T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.


Allowing for uncertainty due to missing and LOCF imputed outcomes in meta-analysis.
The use of the last observation carried forward (LOCF) method for imputing missing outcome data in randomized clinical trials has been much criticized and its shortcomings are well understood. However, only recently have published studies widely started using more appropriate imputation methods. Consequently, meta-analyses often include several studies reporting their results according to LOCF. The results from such meta-analyses are potentially biased and overprecise. We develop methods for estimating summary treatment effects for continuous outcomes in the presence of both missing and LOCF-imputed outcome data. Our target is the treatment effect if complete follow-up was obtained even if some participants drop out from the protocol treatment. We extend a previously developed meta-analysis model, which accounts for the uncertainty due to missing outcome data via an informative missingness parameter. The extended model includes an extra parameter that reflects the level of prior confidence in the appropriateness of the LOCF imputation scheme. Neither parameter can be informed by the data and we resort to expert opinion and sensitivity analysis. We illustrate the methodology using two meta-analyses of pharmacological interventions for depression.


Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone in rats.
Doxorubicin (DXR) is an anthracycline glycoside with a broad spectrum of therapeutic activity against various tumors. However, the clinical use of DXR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of dietary intake of pirfenidone (PD) against DXR-induced cardiac and renal toxicity. Male Sprague Dawley rats were placed into four treatment groups: saline injected intraperitoneally (i.p.) plus regular diet (SA+RD); DXR i.p. plus regular diet (DXR+RD); saline i.p. plus the same diet mixed with 0.6% PD (SA+PD); and DXR i.p. plus the same diet mixed with 0.6% PD (DXR+PD). The animals were fed regular or regular plus PD diets 3 days prior to i.p. injections of either saline or DXR and continuing throughout the study. A total dose of DXR (16.25 mg/kg) or an equivalent volume of saline was administered in seven injections (2.32 mg/kg per injection) three times per week with an additional dose on the 12th day. At 25 days following the last DXR or saline injection, some animals were anesthetized for the measurement of cardiac and pulmonary function, and others were killed by an overdose of pentobarbital. At the time the animals were killed, abdominal fluid was collected. Kidney and heart were removed, weighed, fixed with 10% formalin or frozen in liquid nitrogen. The fixed tissues were used for histological examination and the frozen tissues were used for biochemical studies. The average volumes of abdominal fluid in the DXR+RD and DXR+PD groups were 9.42 ml and 3.42 ml and the protein contents of abdominal fluid in the DXR+RD and DXR+PD groups were 218 mg and 70 mg, respectively. A 12.5% mortality occurred in the DXR+RD group as compared to 0% in DXR+PD group. There were no changes in any of the cardiac or pulmonary physiological parameters in any of the four groups. The changes in the heart and kidney of the DXR+RD group included reduction in organ weight, increase in hydroxyproline content of heart, increase in hydroxyproline, and lipid peroxidation in the kidney and plasma, and increase in protein concentration in urine as compared to rats in the control, SA+RD and SA+PD groups. Treatment with PD abrogated the DXR-induced increases in hydroxyproline content in the heart and kidney, lipid peroxidation of the kidney and plasma, and protein content of the urine in the DXR+PD group. DXR treatment alone caused disorganization of cardiac myofibrils, vacuolization of the myofibers, and renal tubular dilation with protein casts in both the cortical and medullary regions. Treatment with PD minimized the DXR-induced histopathological changes of heart and kidney in the DXR+PD group. Treatment with PD reduced the severity of DXR-induced toxicity as assessed by reduced mortality, diminished volume of recovered fluid in the abdominal cavity, and severity of cardiac and renal lesions at both the biochemical and morphological levels. These results indicate that PD has the potential to prevent DXR-induced cardiac and renal damage in humans on DXR therapy.


The development of a virtual simulator for training neurosurgeons to perform and perfect endoscopic endonasal transsphenoidal surgery.
A virtual reality (VR) neurosurgical simulator with haptic feedback may provide the best model for training and perfecting surgical techniques for transsphenoidal approaches to the sella turcica and cranial base. Currently there are 2 commercially available simulators: NeuroTouch (Cranio and Endo) developed by the National Research Council of Canada in collaboration with surgeons at teaching hospitals in Canada, and the Immersive Touch. Work in progress on other simulators at additional institutions is currently unpublished. This article describes a newly developed application of the NeuroTouch simulator that facilitates the performance and assessment of technical skills for endoscopic endonasal transsphenoidal surgical procedures as well as plans for collecting metrics during its early use. The main components of the NeuroTouch-Endo VR neurosurgical simulator are a stereovision system, bimanual haptic tool manipulators, and high-end computers. The software engine continues to evolve, allowing additional surgical tasks to be performed in the VR environment. Device utility for efficient practice and performance metrics continue to be developed by its originators in collaboration with neurosurgeons at several teaching hospitals in the United States. Training tasks are being developed for teaching 1- and 2-nostril endonasal transsphenoidal approaches. Practice sessions benefit from anatomic labeling of normal structures along the surgical approach and inclusion (for avoidance) of critical structures, such as the internal carotid arteries and optic nerves. The simulation software for NeuroTouch-Endo VR simulation of transsphenoidal surgery provides an opportunity for beta testing, validation, and evaluation of performance metrics for use in neurosurgical residency training. CTA, cognitive task analysisVR, virtual reality.


A Quality Improvement Intervention to Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) in Patients With Chronic Kidney Disease: Clinical Research Protocol of a Cluster-Randomized Clinical Trial.
Many patients with kidney failure will live longer and healthier lives if they receive a kidney transplant rather than dialysis. However, multiple barriers prevent patients from accessing this treatment option. To determine if a quality improvement intervention provided in chronic kidney disease (CKD) programs (vs. usual care) enables more patients with no recorded contraindications to kidney transplant to complete more steps toward receiving a kidney transplant. This protocol describes a pragmatic 2-arm, parallel-group, open-label, registry-based, cluster-randomized clinical trial-the Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) trial. All 26 CKD programs in Ontario, Canada, with a trial start date of November 1, 2017. The original end date of March 31, 2021 (3.4 years) has been extended to December 31, 2021 (4.1 years) due to the COVID-19 pandemic. During the trial, the 26 CKD programs are expected to care for more than 10 000 adult patients with CKD (including patients approaching the need for dialysis and patients receiving dialysis) with no recorded contraindications to a kidney transplant. Programs were randomly allocated to provide a quality improvement intervention or usual care. The intervention has 4 main components: (1) local quality improvement teams and administrative support; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders. The primary outcome is the number of key steps completed toward receiving a kidney transplant analyzed at the cluster level (CKD program). The following 4 unique steps per patient will be counted: (1) patient referred to a transplant center for evaluation, (2) at least one living kidney donor candidate contacts a transplant center for an intended recipient and completes a health history questionnaire to begin their evaluation, (3) patient added to the deceased donor transplant wait list, and (4) patient receives a kidney transplant from a living or deceased donor. Study data will be obtained from Ontario's linked administrative healthcare databases. An intent-to-treat analysis will be conducted comparing the primary outcome between randomized groups using a 2-stage approach. First stage: residuals are obtained from fitting a regression model to individual-level variables ignoring intervention and clustering effects. Second stage: residuals from the first stage are aggregated at the cluster level as the outcome. It may not be possible to isolate independent effects of each intervention component, the usual care group could adopt intervention components leading to contamination bias, and the relatively small number of clusters could mean the 2 arms are not balanced on all baseline prognostic factors. The EnAKT LKD trial will provide high-quality evidence on whether a multi-component quality improvement intervention helps patients complete more steps toward receiving a kidney transplant. Clinicaltrials.gov; identifier: NCT03329521.


Regional differences in estradiol effects on numbers of HSD2-containing neurons in the nucleus of the solitary tract of rats.
Estrogens affect body fluid balance, including sodium ingestion. Recent findings of a population of neurons in the hindbrain nucleus of the solitary tract (NTS) of rats that are activated during sodium need suggest a possible central substrate for this effect of estrogens. We used immunohistochemistry to label neurons in the NTS that express 11-β-hydroxysteroid dehydrogenase type 2 (HSD2), an enzyme that promotes aldosterone binding, in male rats, and in ovariectomized (OVX) rats given estradiol benzoate (EB) or oil vehicle (OIL). During baseline conditions, the number of HSD2 immunoreactive neurons in the NTS immediately rostral to the area postrema was greater in EB-treated OVX rats compared to those in OIL-treated OVX and male rats. A small number of HSD2 immunoreactive neurons was also labeled for dopamine-β-hydroxylase (DBH), an enzyme involved in norepinephrine biosynthesis. Double-labeled neurons in the NTS were located primarily in the more lateral portion of the HSD2 population, at the level of the area postrema in all three groups, with no sex or estrogen-mediated differences in the number of double-labeled neurons. These results suggest that two subpopulations of HSD2 neurons are present in the NTS. One subpopulation, which does not colocalize with DBH and is increased during conditions of elevated estradiol, may contribute to the effects of estrogens on sodium ingestion. The role of the other, smaller subpopulation, which colocalizes with DBH and is not affected by estradiol, remains to be determined, but one possibility is that these latter neurons are part of a larger network of catecholaminergic input to neuroendocrine neurons in the hypothalamus.


Violence-related Versus Terror-related Stabbings: Significant Differences in Injury Characteristics.
To demonstrate the gap between injury epidemiology of terror-related stabbings (TRS) and non-terror-related intentional stabbings. Terror attacks with sharp instruments have multiplied recently, with many victims of these incidents presented to hospitals with penetrating injuries. Because most practical experience of surgeons with intentional stabbing injuries comes from treating victims of interpersonal violence, potential gaps in knowledge may exist if injuries from TRS significantly differ from interpersonal stabbings (IPS). A retrospective study of 1615 patients from intentional stabbing events recorded in the Israeli National Trauma Registry during the period of "Knife Intifada" (January 2013-March 2016). All stabbings were divided into TRS and IPS. The 2 categories were compared in terms of sustained injuries, utilization of hospital resources, and clinical outcomes. TRS patients were older, comprised more females and were ethnically homogenous. Most IPS incidents happened on weekdays and at night hours, whereas TRS events peaked midweek during morning and afternoon hours. TRS patients had more injuries of head, face, and neck, and severe head and neck injuries. IPS patients had more abdomen injuries; however, respective injuries in the TRS group were more severe. Greater injury severity of the TRS patients reflected on their higher hospital resources utilization and greater in-hospital mortality. Victims of terror stabbings are profoundly different in their characteristics, sustain injuries of a different profile and greater severity, require more hospital resources, and have worse off clinical outcomes, emphasizing the need of the healthcare systems to adjust itself appropriately to deal successfully with future terror attacks.


Identification of Novel Human Monocyte Subsets and Evidence for Phenotypic Groups Defined by Interindividual Variations of Expression of Adhesion Molecules.
Monocytes contribute to immune responses as a source for subsets of dendritic cells and macrophages. Human blood monocytes are classified as classical, non-classical and intermediate cells. However, the particular functions of these subsets have been hard to define, with conflicting results and significant overlaps. One likely reason for these ambiguities is in the heterogeneity of these monocyte subsets regrouping cells with divergent functions. To better define monocyte populations, we have analysed expression of 17 markers by multicolour flow cytometry in samples obtained from 28 control donors. Data acquisition was tailored to detect populations present at low frequencies. Our results reveal the existence of novel monocyte subsets detected as larger CD14+ cells that were CD16+ or CD16neg. These large monocytes differed from regular, smaller monocytes with respect to expression of various cell surface molecules, such as FcR, chemokine receptors, and adhesion molecules. Unsupervised multidimensional analysis confirmed the existence of large monocytes and revealed interindividual variations that were grouped according to unique patterns of expression of adhesion molecules CD62L, CD49d, and CD43. Distinct inflammatory responses to TLR agonists were found in small and large monocytes. Overall, refining the definition of monocyte subsets should lead to the identification of populations with specific functions.


Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma.
Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity.


[Potential of plasma adiponectin concentrations as a predictive marker for in-stent restenosis after percutaneous coronary intervention in patients on hemodialysis].
Success of coronary stenting is limited by in-stent restenosis. We aimed to determine whether circulating levels of adiponectin could be associated with the occurrence of coronary in-stent restenosis in patients with end-stage renal disease (ESRD). We enrolled 71 consecutive ESRD patients undergoing hemodialysis (mean age: 64.9 +/- 8.9 years; 19 women, 52 men; mean hemodialysis duration: 78.2 +/- 87.5 months), who received stenting for a single coronary lesion. Plasma adiponectin concentrations were measured within one week before coronary stenting. Of 71 patients who had received stenting, in-stent restenosis occurred in 37 patients (52.1%) within 6 months after stenting. In univariate logistic analysis, homeostasis model assessment index of insulin resistance, blood hemoglobin, serum concentrations of high density lipoprotein cholesterol or triglycerides, and plasma concentrations of insulin or adiponectin were significantly associated with coronary in-stent restenosis. In multiple logistic regression analysis among these variables, however, only the plasma adiponectin concentration was associated with the coronary in-stent restenosis: the odds ratio of increase in 1 microg/ml of plasma adiponectin concentration for having restenosis was 0.651 (p = 0.001, 95% confidence interval: 0.506-0.839). Patients with restenosis had lower plasma adiponectin concentrations than those without [6.2 +/- 2.2 microg/ml (2.1-10.4 microg/ml; n=37) versus 27.2 +/- 10.8 microg/ml (17.9-79.8 microg/ml; n=34); p = 0.0001]. Circulating adiponectin concentrations may be associated with the occurrence of coronary in-stent restenosis in ESRD patients undergoing maintenance hemodialysis.


Differential effects of leukotrienes C4, D4 and E4 in the canine renal and mesenteric vascular beds.
Although leukotrienes (LTs) have been studied extensively with regard to their influence in the lung and the heart, little is known about the actions of these agents in other important vascular beds. In this study, effects of close-arterial injections of synthetic LTs C4, D4 and E4 were determined in the renal and superior mesenteric vascular beds of anesthetized dogs. In the mesenteric circulation, 0.01 to 0.3 microgram of LTC4 and LTD4 reduced blood flow 20 to 60%. Effects were rapid in onset and flow returned to base line within 2 to 3 min. LTE4 was less potent in the mesenteric circulation and responses were not clearly dose dependent over the same range. In contrast, renal blood flow increased after injections of 3 and 10 micrograms of LTC4 and LTD4 into the renal artery. LTE4 did not influence renal blood flow significantly at these doses. Inhibition of prostaglandin synthesis did not alter responses to these LTs in either vascular bed, suggesting that endogenous prostaglandin synthesis did not mediate or modulate responses to the LTs. Mesenteric vascular responses to LTC4 and LTD4, but not LTE4, were inhibited by the LT receptor antagonist FPL-55712. Because LTs are released in a variety of immunological and inflammatory reactions, their differential effects may lead to a redistribution of peripheral blood flow in these reactions.


Plasma endothelial cell-specific molecule-1 (ESM-1) in management of community-acquired pneumonia.
Endothelial cell-specific molecule (ESM)-1 is a soluble proteoglycan expressed by the vascular endothelium and which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels are found in immunocompetent patients with sepsis. The aim of this study was to investigate differential changes in plasma levels of ESM-1 before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). Plasma ESM-1 levels were measured in 82 adult patients with CAP and 82 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, Acute Physiology and Chronic Health Evaluation II (APACHE II), CURB-65, and Pneumonia Severity Index (PSI) scores were determined to assess CAP severity in these patients. Results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of C-reactive protein (CRP) and ESM-1 after antibiotic treatment. The plasma concentration of ESM-1, but not CRP or the WBC count, was correlated with the severity of CAP based on the PSI (r=0.554, p<0.001), CURB-65 (r=0.510, p<0.001), and APACHE II scores (r=0.447, p<0.001). Plasma levels of ESM-1 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.


Dental care coverage and use: modeling limitations and opportunities.
We examined why older US adults without dental care coverage and use would have lower use rates if offered coverage than do those who currently have coverage. We used data from the 2008 Health and Retirement Study to estimate a multinomial logistic model to analyze the influence of personal characteristics in the grouping of older US adults into those with and those without dental care coverage and dental care use. Compared with persons with no coverage and no dental care use, users of dental care with coverage were more likely to be younger, female, wealthier, college graduates, married, in excellent or very good health, and not missing all their permanent teeth. Providing dental care coverage to uninsured older US adults without use will not necessarily result in use rates similar to those with prior coverage and use. We have offered a model using modifiable factors that may help policy planners facilitate programs to increase dental care coverage uptake and use.


Global health systems partnerships: a mixed methods analysis of Mozambique's HPV vaccine delivery network actors.
Global health partnerships have expanded exponentially in the last two decades with Gavi, the Vaccine Alliance considered the model's pioneer and leader because of its vaccination programs' implementation mechanism. Gavi, relies on diverse domestic and international partners to carry out the programs in low- and middle-income countries under a partnership engagement framework (PEF). In this study, we utilized mixed methods to examine Mozambique's Gavi driven partnership network which delivered human papillomavirus (HPV) vaccine during the demonstration phase. Qualitative tools gauged contextual factors, prerequisites, partner performance and practices while a social network analysis (SNA) survey measured the partnership structure and perceived added value in terms of effectiveness, efficiency and country ownership. Forty key informants who were interviewed included frontline Ministry of Health workers, Ministry of Education staff and supporting partner organization members, of whom 34 participated in the social network analysis survey. Partnership structure SNA connectivity measurement scores of reachability (100%) and average distance (2.5), were high, revealing a network of very well-connected HPV vaccination implementation collaborators. Such high scores reflect a network structure favorable for rapid and widespread diffusion of information, features necessary for engaging and handling multiple implementation scales. High SNA effectiveness and efficiency measures for structural holes (85%) and low redundancy (30%) coupled with high mean perceived effectiveness (97.6%) and efficiency (79.5%) network outcome scores were observed. Additionally, the tie strength average score of 4.1 on a scale of 5 denoted high professional trust. These are all markers of a collaborative partnership environment in which disparate institutions and organizations leveraged each entity's comparative advantage. Lower perceived outcome scores for country ownership (24%) were found, with participants citing the prominent role of several out-of-country partner organizations as a major obstacle. While there is room for improvement on the country ownership aspects of the partnership, the expanded, diverse and inclusive collaboration of institutions and organizations that implemented the Mozambique HPV vaccine demonstration project was effective and efficient. We recommend that the country adapt a similar model during national scale up of HPV vaccination.


Frequency-dependent selection: the high potential for permanent genetic variation in the diallelic, pairwise interaction model.
A detailed analytic and numerical study is made of the potential for permanent genetic variation in frequency-dependent models based on pairwise interactions among genotypes at a single diallelic locus. The full equilibrium structure and qualitative gene-frequency dynamics are derived analytically for a symmetric model, in which pairwise fitnesses are chiefly determined by the genetic similarity of the individuals involved. This is supplemented by an extensive numerical investigation of the general model, the symmetric model, and nine other special cases. Together the results show that there is a high potential for permanent genetic diversity in the pairwise interaction model, and provide insight into the extent to which various forms of genotypic interactions enhance or reduce this potential. Technically, although two stable polymorphic equilibria are possible, the increased likelihood of maintaining both alleles, and the poor performance of protected polymorphism conditions as a measure of this likelihood, are primarily due to a greater variety and frequency of equilibrium patterns with one stable polymorphic equilibrium, in conjunction with a disproportionately large domain of attraction for stable internal equilibria.


The long-term effect of posterolateral fusion in adult isthmic spondylolisthesis: a randomized controlled study.
Today there is some evidence-based medicine support for a positive short-term treatment effect of fusion in chronic low back pain in spondylolisthesis and in nonspecific degenerative lumbar spine disorders. The long-term effect is, however, unknown. To determine the long-term outcome of lumbar fusion in adult isthmic spondylolisthesis. Prospective, randomized controlled study comparing a 1-year exercise program with instrumented and non-instrumented posterolateral fusion with average long-term follow-up of 9 years (range, 5-13). 111 patients aged 18 to 55 years with adult lumbar isthmic spondylolisthesis at L5 or L4 level of all degrees, and at least 1-year's duration of severe lumbar pain with or without sciatica. Pain and functional disability was quantified by pain (VAS), the Disability Rating Index (DRI), the Oswestry Disability Index (ODI) work status, and global assessment of outcome by the patient into much better, better, unchanged or worse. Quality of life was assessed by the SF-36. The patients were randomly allocated to treatment with 1) a 1-year exercise program (n=34), 2) posterolateral fusion without pedicle screw instrumentation (n=37), or 3) posterolateral fusion with pedicle screw instrumentation (n=40). Long-term follow-up was obtained in 101 (91%) patients. Nine patients in the exercise group were eventually operated on. Longitudinal analysis: At long-term follow-up pain and functional disability were significantly better than before treatment in both surgical groups. No significant differences were observed between instrumented and non-instrumented patients in any variable studied. In the exercise group the pain was significantly reduced but not the functional disability. Compared with the 2-year follow-up a significant increase in functional disability was observed, as measured by the DRI, but not the ODI, in the surgical group at long term. In the exercise group no significant changes were observed between the 2-year and the long-term follow-up. Cross-sectional analysis: Between the surgical and conservative group no significant differences were observed in any outcome measurement at long-term follow-up except for global assessment, which was significantly better for surgical patients. Of surgical patients 76% classified the overall outcome as much better or better compared with 50% of conservatively treated patients (p=0.015). Quality of life as estimated by the SF-36 at long term was not different between treatment groups in any of the eight domains studied but was considerably lower than for the normal population. Posterolateral fusion in adult lumbar isthmic spondylolisthesis results ina modestly improved long-term outcome compared with a 1-year exercise program. Although the results show that some of the previously reported short-term improvement is lost at long term, patients with fusion still classify their global outcome as clearly better than conservatively treated patients. Furthermore, because the long-term outcome of the patients conservatively treated most likely reflects the natural course, one can also conclude that no considerable spontaneous improvement should be expected over time in adult patients with symptomatic isthmic spondylolisthesis. Substantial pain, functional disability and a reduced quality of life will in most patients most likely remain unaltered over many years.


Global selection of Plasmodium falciparum virulence antigen expression by host antibodies.
Parasite proteins called PfEMP1 that are inserted on the surface of infected erythrocytes, play a key role in the severe pathology associated with infection by the Plasmodium falciparum malaria parasite. These proteins mediate binding of infected cells to the endothelial lining of blood vessels as a strategy to avoid clearance by the spleen and are major targets of naturally acquired immunity. PfEMP1 is encoded by a large multi-gene family called var. Mutually-exclusive transcriptional switching between var genes allows parasites to escape host antibodies. This study examined in detail the patterns of expression of var in a well-characterized sample of parasites from Kenyan Children. Instead of observing clear inverse relationships between the expression of broad sub-classes of PfEMP1, we found that expression of different PfEMP1 groups vary relatively independently. Parasite adaptation to host antibodies also appears to involve a general reduction in detectable var gene expression. We suggest that parasites switch both between different PfEMP1 variants and between high and low expression states. Such a strategy could provide a means of avoiding immunological detection and promoting survival under high levels of host immunity.


Generation of a restriction fragment length polymorphism linkage map for Toxoplasma gondii.
We have constructed a genetic linkage map for the parasitic protozoan, Toxoplasma gondii, using randomly selected low copy number DNA markers that define restriction fragment length polymorphisms (RFLPs). The inheritance patterns of 64 RFLP markers and two phenotypic markers were analyzed among 19 recombinant haploid progeny selected from two parallel genetic crosses between PLK and CEP strains. In these first successful interstrain crosses, these RFLP markers segregated into 11 distinct genetic linkage groups that showed close correlation with physical linkage groups previously defined by molecular karyotype. Separate linkage maps, constructed for each of the 11 chromosomes, indicated recombination frequencies range from approximately 100 to 300 kb per centimorgan. Preliminary linkage assignments were made for the loci regulating sinefungin resistance (snf-1) on chromosome IX and adenine arabinoside (ara-1) on chromosome V by linkage to RFLP markers. Despite random segregation of separate chromosomes, the majority of chromosomes failed to demonstrate internal recombination events and in 3/19 recombinant progeny no intramolecular recombination events were detected. The relatively low rate of intrachromosomal recombination predicts that tight linkage for unknown genes can be established with a relatively small set of markers. This genetic linkage map should prove useful in mapping genes that regulate drug resistance and other biological phenotypes in this important opportunistic pathogen.


Feasibility of a bilateral 4000-6000 Hz notch as a phenotype for genetic association analysis.
Noise-induced hearing loss (NIHL) is a worldwide health problem and a growing concern among young people. Although some people appear to be more susceptible to NIHL, genetic association studies lack a specific phenotype. We tested the feasibility of a bilateral 4000-6000 Hz audiometric notch as a phenotype for identifying genetic contributions to hearing loss in young adults. A case-control-control study was conducted to examine selected SNPs in 52 genes previously associated with hearing loss and/or expressed in the cochlea. A notch was defined as a minimum of a 15-dB drop at 4000-6000 Hz from the previous best threshold with a 5-dB 'recovery' at 8000 Hz. Participants were 252 individuals of European descent taken from a population of 640 young adults who are students of classical music. Participants were grouped as No-notch (NN), Unilateral Notch (UN), or Bilateral Notch (BN). The strongest evidence of a genetic association with the 4000-6000 Hz notch was a nonsynonymous SNP variant in the ESRR- gene (rs61742642:C> T, P386S). Carriers of the minor allele accounted for 26% of all bilateral losses. This study indicates that the 4000-6000 Hz bilateral notch is a feasible phenotype for identifying genetic susceptibility to hearing loss.


Tracking Multiple Genomic Elements Using Correlative CRISPR Imaging and Sequential DNA FISH.
Live imaging of genome has offered important insights into the dynamics of the genome organization and gene expression. The demand to image simultaneously multiple genomic loci has prompted a flurry of exciting advances in multicolor CRISPR imaging, although color-based multiplexing is limited by the need for spectrally distinct fluorophores. Here we introduce an approach to achieve highly multiplexed live recording via correlative CRISPR imaging and sequential DNA fluorescence in situ hybridization (FISH). This approach first performs one-color live imaging of multiple genomic loci and then uses sequential rounds of DNA FISH to determine the loci identity. We have optimized the FISH protocol so that each round is complete in 1 min, demonstrating the identification of seven genomic elements and the capability to sustain reversible staining and washing for up to 20 rounds. We have also developed a correlation-based algorithm to faithfully register live and FISH images. Our approach keeps the rest of the color palette open to image other cellular phenomena of interest, as demonstrated by our simultaneous live imaging of genomic loci together with a cell cycle reporter. Furthermore, the algorithm to register faithfully between live and fixed imaging is directly transferrable to other systems such as multiplex RNA imaging with RNA-FISH and multiplex protein imaging with antibody-staining.


Developing a Value-Based Approach to Outcome Reporting in Pediatric Surgery.
The population that undergoes pediatric surgical procedures in high-resource settings such as Canada primarily comprises healthy patients who undergo low-risk, elective surgeries and fewer higher-risk patients who require more complex surgeries. Given this variability, there is a relatively low incidence of traditionally measured "critical" outcomes within any single pediatric surgical system or even pediatric surgical subspecialty, rendering the currently available quality measurement tools inadequate to provide sensitive measures of quality. In an era when scalable solutions are required to improve health outcomes across entire populations, there is an urgent need for more holistic measures of a child's well-being to benchmark and measure changes in quality of care. This article discusses opportunities for enhanced performance measurement in pediatric surgery using a value-based framework to identify and measure patient and family outcomes of importance over the full care cycle, from initial presentation through surgery and recovery to sustainability of health. In suggesting new avenues for performance measurement, we highlight how these measures can be used to develop, evaluate and refine surgical system innovations such as bundled care pathways and perioperative care homes.


Radio emission from an ultraluminous x-ray source.
The physical nature of ultraluminous x-ray sources is uncertain. Stellar-mass black holes with beamed radiation and intermediate black holes with isotropic radiation are two plausible explanations. We discovered radio emission from an ultraluminous x-ray source in the dwarf irregular galaxy NGC 5408. The x-ray, radio, and optical fluxes as well as the x-ray spectral shape are consistent with beamed relativistic jet emission from an accreting stellar black hole. If confirmed, this would suggest that the ultraluminous x-ray sources may be stellar-mass rather than intermediate-mass black holes. However, interpretation of the source as a jet-producing intermediate-mass black hole cannot be ruled out at this time.


Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study.
Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels. Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from enrollees were homogenized and profiled for gene expression across a panel of candidate genes, including known arsenic regulated targets and genes involved in arsenic transport, metabolism, or disease susceptibility. Multivariable adjusted linear regression models were used to examine the relationship of candidate gene expression with arsenic exposure or with birth weight of the baby. Placental expression of the arsenic transporter AQP9 was positively associated with maternal urinary arsenic levels during pregnancy (coefficient estimate: 0.25; 95% confidence interval: 0.05 - 0.45). Placental expression of AQP9 related to expression of the phospholipase ENPP2 which was positively associated with infant birth weight (coefficient estimate: 0.28; 95% CI: 0.09 - 0.47). A structural equation model indicated that these genes may mediate arsenic's effect on infant birth weight (coefficient estimate: -0.009; 95% confidence interval: -0.032 - -0.001; 10,000 replications for bootstrapping). We identified the expression of AQP9 as a potential fetal biomarker for arsenic exposure. Further, we identified a positive association between the placental expression of phospholipase ENPP2 and infant birth weight. These findings suggest a path by which arsenic may affect birth outcomes.


Exogenous signal-independent nuclear IkappaB kinase activation triggered by Nkx3.2 enables constitutive nuclear degradation of IkappaB-alpha in chondrocytes.
NF-κB is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-κB can be activated in response to various stimuli. While signal-inducible NF-κB activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-κB activation processes remain poorly understood. Here we show that IκB kinase β (IKKβ) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKKγ) can give rise to constitutive IKKβ activation in the nucleus. Once the Nkx3.2-NEMO-IKKβ complex is formed in the nucleus, IKKβ-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows βTrCP to be engaged to cause IκB-α ubiquitination independent of IκB-α phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of IκB in the nucleus in the absence of exogenous NF-κB-activating signals, which, in turn, plays a role in chondrocyte viability maintenance.


NFY or a related CCAAT binding factor can be replaced by other transcriptional activators for co-operation with HNF1 in driving the rat albumin promoter in vivo.
Like many eukaryotic genes, the rat albumin promoter contains a CCAAT consensus motif at position -80. In transfected H4II hepatoma cells the strength of this promoter depends to a large extent on the integrity of a hepatic nuclear factor 1 (HNF1) binding site located at position -60 and to a lesser extent on the CCAAT element. However, if the affinity for HNF1 is reduced, the CCAAT-box becomes essential for high, and tissue specific, promoter activity. We wished to determine which, among the different CCAAT binding factors co-existing in eukaryotic cells, was responsible for this co-operativity with HNF1. To this end we prepared a series of mutants of the CCAAT sequence and compared their effects on albumin promoter activity in vivo and on the binding of different CCAAT binding factors in vitro. Our results strongly suggest that a ubiquitous factor NFY (also designated CBF, ACF, CP1) interacts with this CCAAT element in vivo. We propose that during development NFY could facilitate transcription of the albumin gene in hepatocytes when the concentration of HNF1 is limiting. This co-operativity in transcriptional activation is not due to strict co-operativity in DNA binding between the two proteins and is not limited to NFY or a closely related factor, as the CCAAT-box can be replaced by AP1, SP1 or E2 target sites without significantly affecting the final activity.


Protein lipoylation in mitochondria requires Fe-S cluster assembly factors NFU4 and NFU5.
Plants have evolutionarily conserved NifU (NFU)-domain proteins that are targeted to plastids or mitochondria. "Plastid-type" NFU1, NFU2, and NFU3 in Arabidopsis (Arabidopsis thaliana) play a role in iron-sulfur (Fe-S) cluster assembly in this organelle, whereas the type-II NFU4 and NFU5 proteins have not been subjected to mutant studies in any plant species to determine their biological role. Here, we confirmed that NFU4 and NFU5 are targeted to the mitochondria. The proteins were constitutively produced in all parts of the plant, suggesting a housekeeping function. Double nfu4 nfu5 knockout mutants were embryonic lethal, and depletion of NFU4 and NFU5 proteins led to growth arrest of young seedlings. Biochemical analyses revealed that NFU4 and NFU5 are required for lipoylation of the H proteins of the glycine decarboxylase complex and the E2 subunits of other mitochondrial dehydrogenases, with little impact on Fe-S cluster-containing respiratory complexes or aconitase. Consequently, the Gly-to-Ser ratio was increased in mutant seedlings and early growth improved with elevated CO2 treatment. In addition, pyruvate, 2-oxoglutarate, and branched-chain amino acids accumulated in nfu4 nfu5 mutants, further supporting defects in the other three mitochondrial lipoate-dependent enzyme complexes. NFU4 and NFU5 interacted with mitochondrial lipoyl synthase (LIP1) in yeast 2-hybrid and bimolecular fluorescence complementation assays. These data indicate that NFU4 and NFU5 have a more specific function than previously thought, most likely providing Fe-S clusters to lipoyl synthase.


Close genetic relationships between a spousal pair with autism-affected children and high minor allele content in cases in autism-associated SNPs.
Parents of children affected with autism spectrum disorders (ASD) often have mild forms of autistic-like characteristics. Past studies have focused on searching for individual genetic risk loci of ASD. Here we studied the overall properties of the genomes of ASD trios by using previously published genome-wide data for common SNPs. The pairwise genetic distance (PGD) between a spousal pair with ASD-affected children was found smaller than that of a random pair selected among the spouses in the ASD trios, and spousal relatedness correlated with severe forms of ASD. Furthermore, for a set of 970 ASD associated SNPs, cases showed higher homozygous minor allele content than parents. These results indicate new genetic elements in the broad phenotypes of parents with ASD-affected offspring and in ASD pathogenesis.


Geometry and topology of the space of sonar target echos.
Successful synthetic aperture sonar target classification depends on the "shape" of the scatterers within a target signature. This article presents a workflow that computes a target-to-target distance from persistence diagrams, since the "shape" of a signature informs its persistence diagram in a structure-preserving way. The target-to-target distances derived from persistence diagrams compare favorably against those derived from spectral features and have the advantage of being substantially more compact. While spectral features produce clusters associated to each target type that are reasonably dense and well formed, the clusters are not well-separated from one another. In rather dramatic contrast, a distance derived from persistence diagrams results in highly separated clusters at the expense of some misclassification of outliers.


Effect of Educational Outreach Timing and Duration on Facility Performance for Infectious Disease Care in Uganda: A Trial with Pre-Post and Cluster Randomized Controlled Components.
Classroom-based learning is often insufficient to ensure high quality care and application of health care guidelines. Educational outreach is garnering attention as a supplemental method to enhance health care worker capacity, yet there is little information about the timing and duration required to improve facility performance. We sought to evaluate the effects of an infectious disease training program followed by either immediate or delayed on-site support (OSS), an educational outreach approach, on nine facility performance indicators for emergency triage, assessment, and treatment; malaria; and pneumonia. We also compared the effects of nine monthly OSS visits to extended OSS, with three additional visits over six months. This study was conducted at 36 health facilities in Uganda, covering 1,275,960 outpatient visits over 23 months. From April 2010 to December 2010, 36 sites received infectious disease training; 18 randomly selected sites in arm A received nine monthly OSS visits (immediate OSS) and 18 sites in arm B did not. From March 2011 to September 2011, arm A sites received three additional visits every two months (extended OSS), while the arm B sites received eight monthly OSS visits (delayed OSS). We compared the combined effect of training and delayed OSS to training followed by immediate OSS to determine the effect of delaying OSS implementation by nine months. We also compared facility performance in arm A during the extended OSS to immediate OSS to examine the effect of additional, less frequent OSS. Delayed OSS, when combined with training, was associated with significant pre/post improvements in four indicators: outpatients triaged (44% vs. 87%, aRR = 1.54, 99% CI = 1.11, 2.15); emergency and priority patients admitted, detained, or referred (16% vs. 31%, aRR = 1.74, 99% CI = 1.10, 2.75); patients with a negative malaria test result prescribed an antimalarial (53% vs. 34%, aRR = 0.67, 99% CI = 0.55, 0.82); and pneumonia suspects assessed for pneumonia (6% vs. 27%, aRR = 2.97, 99% CI = 1.44, 6.17). Differences between the delayed OSS and immediate OSS arms were not statistically significant for any of the nine indicators (all adjusted relative RR (aRRR) between 0.76-1.44, all p>0.06). Extended OSS was associated with significant improvement in two indicators (outpatients triaged: aRR = 1.09, 99% CI = 1.01; emergency and priority patients admitted, detained, or referred: aRR = 1.22, 99% CI = 1.01, 1.38) and decline in one (pneumonia suspects assessed for pneumonia: aRR: 0.93; 99% CI = 0.88, 0.98). Educational outreach held up to nine months after training had similar effects on facility performance as educational outreach started within one month post-training. Six months of bi-monthly educational outreach maintained facility performance gains, but incremental improvements were heterogeneous.


Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States.
The aim of this study was to determine the frequency and the severity of pancreatitis after EUS-guided FNA of solid pancreatic masses. A survey of centers that offer training in EUS in the United States was conducted. A list of centers in which training in EUS is offered was obtained from the Web site of the American Society for Gastrointestinal Endoscopy. Designated program directors were contacted via e-mail. The information requested included the number of EUS-guided FNA procedures performed for solid pancreatic masses, the number of cases of post-procedure pancreatitis, and the method for tracking complications. For each episode of pancreatitis, technical details were obtained about the procedure, including the location of the mass, the type of fine needle used, the number of needle passes, and the nature of the lesion. Nineteen of the 27 programs contacted returned the questionnaire (70%). In total, 4909 EUS-guided FNAs of solid pancreatic masses were performed in these 19 centers over a mean of 4 years (range 11 months to 9 years). Pancreatitis occurred after 14 (0.29%): 95% CI[0.16, 0.48] procedures. At two centers in which data on complications were prospectively collected, the frequency of acute pancreatitis was 0.64%, suggesting that the frequency of pancreatitis in the retrospective cohort (0.26%) was under-reported (p=0.22). The odds that cases of pancreatitis would be reported were 2.45 greater for the prospective compared with the retrospective cohort (95% CI[0.55, 10.98]). The median duration of hospitalization for treatment of pancreatitis was 3 days (range 1-21 days). The pancreatitis was classified as mild in 10 cases, moderate in 3, and severe in one; one death (proximate cause, pulmonary embolism) occurred after the development of pancreatitis in a patient with multiple comorbid conditions. EUS-guided FNA of solid pancreatic masses is infrequently associated with acute pancreatitis. The procedure appears to be safe when performed by experienced endosonographers. The frequency of post EUS-guided FNA pancreatitis may be underestimated by retrospective analysis.


Effect on clinical outcome of breast feeding during acute diarrhoea.
The effects of oral rehydration fluid alone and of oral rehydration fluid plus breast feeding on the course and outcome of acute diarrhoea were assessed in two groups of 26 children aged under 2 years. Children who continued to be breast fed during treatment with oral rehydration solutions passed significantly fewer diarrhoeal stools. They also passed, on average, a smaller volume of diarrhoeal stools and recovered from diarrhoea sooner after the start of treatment. Their requirement for oral rehydration fluid was significantly reduced. Breast feeding exerts a beneficial effect on the course and outcome of acute diarrhoea by reducing the number and volume of diarrhoeal stools.


The Nanosized Dye Adsorbents for Water Treatment.
Clean water is a vital element for survival of any living creature and, thus, crucially important to achieve largely and economically for any nation worldwide. However, the astonishingly fast trend of industrialization and population growth and the arisen extensive water pollutions have challenged access to clean water across the world. In this regard, 1.6 million tons of dyes are annually consumed. Thereof, 10%-15% are wasted during use. To decolorize water streams, there is an urgent need for the advanced remediation approaches involving utilization of novel materials and technologies, which are cost and energy efficient. Nanomaterials, with their outstanding physicochemical properties, can potentially resolve the challenge of need to water treatment in a less energy demanding manner. In this review, a variety of the most recent (from 2015 onwards) opportunities arisen from nanomaterials in different dimensionalities, performances, and compositions for water decolorization is introduced and discussed. The state-of-the-art research studies are presented in a classified manner, particularly based on structural dimensionality, to better illustrate the current status of adsorption-based water decolorization using nanomaterials. Considering the introduction of many newly developed nano-adsorbents and their classification based on the dimensionality factor, which has never been employed for this sake in the related literature, a comprehensive review will be presented.


Bond Strength and Cytotoxicity of a Universal Adhesive According to the Hybridization Strategies to Dentin.
This study evaluated application protocol (etch-and-rinse/ER and self-etching/SE) and dentin wettability (wet and dry) on microtensile bond strength (μTBS) and transdentinal cytotoxicity of ScotchbondTM Universal (SU) adhesive system. The μTBS values and fracture mode were registered 24 h after adhesive system application and resin composite block build-up (n=5). For analysis of transdentinal cytotoxicity, odontoblast-like MDPC-23 cells were seeded on pulpal surface of dentin discs (0.4 mm thick) adapted to artificial pulp chambers (n=8). The adhesive system was applied to occlusal surface, followed by 24-h incubation time. Cell viability (Alamar Blue) and morphology (SEM) were assessed. Adper Single Bond 2 and Clearfil SE Bond were used as positive controls of the ER and SE application protocols, respectively. No treatment was performed on negative control (NC) group. Data were analyzed by ANOVA and Tukey's tests (α=5%). Higher μTBS values were found for ER mode in comparison with SE protocol (p<0.05). Dentin wettability had no effect on bond strength of SU in both the ER and SE techniques (p>0.05). Most fractures involved hybrid layer and/or adhesive layer. Neither variable prevented the intense toxic effects of adhesive systems on MDPC-23 cultured cells, since intense reduction in cell viability (±88%) and severe alterations in cell morphology were observed for all groups compared to NC, with no differences among them (p>0.05). Therefore, it was concluded that application of SU following the ER protocol had better adhesive performance. However, this adhesive system featured intense transdentinal cytotoxicity to pulp cells, regardless of application protocol and dentin wettability.