Survival of patients with multidrug-resistant TB in Eastern Europe: what makes a difference?
The quality of care for patients with TB in Eastern Europe has improved significantly; nevertheless drug resistance rates remain high. We analysed survival in a cohort of patients with multidrug-resistant and extensively drug-resistant (MDR-/XDR-) TB from Latvia, Lithuania, Estonia and Bucharest city. Consecutive adult new and retreatment patients with culture-confirmed pulmonary MDR-TB registered for treatment in 2009 (and in 2007 in Latvia) were enrolled; prospective survival information was collected. A total of 737 patients were included into the cohort. Of all MDR-TB cases, 46% were newly diagnosed; 56% of all MDR-TB cases had no additional resistance to fluoroquinolones or injectable agents, 33% had pre-XDR-TB and 11% XDR-TB. Median survival was 5.9 years in patients with MDR-TB and XDR-TB; 1.9 years in patients coinfected with HIV. Older age, male gender, alcohol abuse, retirement, co-morbidities, extrapulmonary involvement and HIV coinfection independently worsened survival. Inclusion of fluoroquinolones and injectable agents improves survival in patients with MDR-TB. Pre-XDR and XDR status did not significantly shorten survival as long as fluoroquinolones and injectable agents were part of the regimen. Moxifloxacin seems to improve survival in ofloxacin-susceptible patients when compared with older generation fluoroquinolones. The burden of additional resistances in patients with MDR-TB is high likely due to primary transmission of resistant strains. Social and programmatic factors including management of alcohol dependency, expansion of HIV testing and antiretroviral treatment need to be addressed in order to achieve cure and to interrupt transmission. The role of last generation fluoroquinolones and injectable agents in treatment of patients with pre-XDR and XDR-TB needs to be further investigated.


[Nucleoli and nucleolus-like bodies in oogenesis stained by silver nitrate].
The nuclear structures were studied in oocytes of two frog species (Rana temporaria and R. ridibunda) in oocytes and trophocytes of three insect species (Blaps lethifera, Laspeyresia pomonella and Chrysopa perla) by the AgNO3-staining method (Howell, Black, 1980). The previously investigated nucleoli of the insect trophocytes and the extra-r-DNA bodies of Chrysopa oocytes were used as test objects. It is demonstrated that in oogenesis, contrary to somatic cells, AgNO3 impregnates both transcriptionally active nucleoli and inactive nuclear structures: extra-r-DNA bodies, nucleolus-like bodies (NLB) and some microbodies. The relationship of Ag+ NLB and microbodies to nucleolar structures is discussed in addition to the role of the r-DNA compactness for the Ag+ reaction.


Pharmacokinetics and pharmacodynamics of piperaquine in a murine malaria model.
Piperaquine (PQ) is an important partner in antimalarial treatment strategies. However, there is a paucity of detailed preclinical and pharmacokinetic data to link PQ serum concentrations and toxicity or efficacy. The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of PQ in a murine malaria treatment model. The study comprised three arms. (i) PQ pharmacokinetic parameters were determined in healthy and malaria-infected mice (90 mg/kg PQ phosphate [PQP]). (ii) For determination of single-dose pharmacodynamics, Swiss mice were inoculated with Plasmodium berghei parasites and given PQP (10, 30, or 90 mg/kg intraperitoneally) at 2 to 5% starting parasitemia. After 60 days, the 90-mg/kg PQP group was reinoculated with P. berghei. (iii) Combination efficacy was investigated at doses of 10 mg/kg PQP and 30 mg/kg dihydroartemisinin (DHA). The median survival times were 4, 10, and 54 days for 0, 10, and 30 mg/kg PQP, respectively. All mice given 90 mg/kg PQP survived beyond 60 days, with a mean parasitemia of <1% before and after reinoculation. The nadir for DHA plus PQP was significantly lower (22-fold +/- 12-fold) than the initial parasitemia for the individual drugs (DHA, 12-fold +/- 5-fold; PQP, 13-fold +/- 3-fold; P = 0.007 [analysis of variance]). The elimination half-lives of PQ in healthy and infected mice were 18 and 16 days, respectively, and the extrapolated residual PQ concentration at 60 days (<10 mug/liter) was ineffective at suppressing P. berghei infection. PQ has a potent antimalarial effect after single-dose treatment, and its efficacy was enhanced by combination with DHA.


Role of Two-Dimensional Speckle-Tracking Echocardiography in Early Detection of Left Ventricular Dysfunction in Dogs.
Two-dimensional speckle-tracking echocardiography (2D-STE) is an advanced echocardiographic technique based on deformation imaging that allows comprehensive evaluation of the myocardial function. Clinical application of 2D-STE holds great potential for its ability to provide valuable information on both global and regional myocardial function and to quantify cardiac rotation and synchronicity, which are not readily possible with the conventional echocardiography. It has gained growing importance over the past decade, especially in human medicine, and its application includes assessment of myocardial function, detection of subclinical myocardial dysfunction and serving as a prognostic indicator. This review illustrates the fundamental concepts of deformation analysis and gives an overview of the current understanding and its clinical application of this technique in veterinary medicine, with a focus on early detection of left ventricular (LV) dysfunction in dogs.


Interaction of anesthetic supplement thiopental with human serum albumin.
Thiopental (TPL) is a commonly used barbiturate anesthetic. Its binding with human serum albumin (HSA) was studied to explore the anesthetic-induced protein dysfunction. The basic binding interaction was studied by UV-absorption and fluorescence spectroscopy. An increase in the binding affinity (K) and in the number of binding sites (n) with the increasing albumin concentration was observed. The interaction was conformation-dependent and the highest for the F isomer of HSA, which implicates its slow elimination. The mode of binding was characterized using various thermodynamic parameters. Domain II of HSA was found to possess a high affinity binding site for TPL. The effect of micro-metal ions on the binding affinity was also investigated. The molecular distance, r, between donor (HSA) and acceptor (TPL) was estimated by fluorescence resonance energy transfer (FRET). Correlation between the stability of the TPL-N and TPL-F complexes and drug distribution is discussed. The structural changes in the protein investigated by circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy reflect perturbation of the albumin molecule and provide an explanation for the heterogeneity of action of this anesthetic.


Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function.
Integration of the proviral DNA intermediate into the host cell genome normally represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that human immunodeficiency virus 1 (HIV-1) mutants lacking a functional integrase (IN) can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1 (HTLV-1). In these cells, HIV-1 forms episomal DNA circles, analogous to hepatitis B virus (HBV) covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. In the presence of Tax, induced NF-κB proteins are recruited to the long terminal repeat (LTR) promoters present on unintegrated HIV-1 DNA, and this recruitment in turn correlates with the loss of inhibitory epigenetic marks and the acquisition of activating marks on histones bound to viral DNA. Therefore, HIV-1 is capable of replication in the absence of integrase function if the epigenetic silencing of unintegrated viral DNA can be prevented or reversed.IMPORTANCE While retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents or reverses the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks and the recruitment of NF-κB/Rel proteins to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic integrase-deficient (IN-) HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV. Moreover, these data suggest that integrase inhibitors may be less effective in the treatment of HIV-1 infections in individuals who are also coinfected with HTLV-1.


Correlation of mutation status and survival with predominant histologic subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification in stage III (N2) patients.
We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom's OncoCarta Panel (v1.0; Sequenom, San Diego, CA). The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) (p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) (p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22-0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR-mutant micropapillary predominant tumors had similar survival to those with EGFR-mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.


Tailored Explanation: A Strategy to Minimize Nonresponse in Demographic Items Among Low-income Racial and Ethnic Minorities.
There is a high rate of nonresponse for demographic items in survey research, particularly for racial and ethnic minority respondents. This present study examined whether providing an explanation to racial and ethnic minority respondents prior to asking a set of demographic questions would increase respondents' motivation to reduce nonresponse to gender, income, age, and race items. Using a cross-sectional, randomized comparison design, 99 respondents were randomly assigned to two groups. Group 1 did not receive an explanation for asking the demographic questions. Group 2 received an explanation designed to be relevant and meaningful to them concerning the significance and potential use of demographic information for racial and ethnic minority populations. A proportional difference test was used to calculate the differences in the proportion of respondents' motivation to complete demographic survey items between the groups. A proportional difference effect size (Cohen's h effect size) was used to determine the magnitude of difference between the two groups. Over 50% of respondents were African Americans. While none of the item non-responses for both groups is statistically significant in terms of proportional differences, there is small (Cohen's h= 0.184) to moderate (Cohen's h=0.342) effect in reducing demographic item non-response when an explanation was provided to respondents. Specifically, adding an explanation made the biggest improvement in reporting income. The study findings support the importance of providing participants with an explanation that is relevant and meaningful to increase motivation and thereby minimize item nonresponse.


Magntic susceptibility as a proxy to heavy metal content in the sediments of Anzali wetland, Iran.
Heavy metal concentrations and magnetic susceptibility of sediment samples were analyzed as indicators of urban and industrial contamination in Anzali wetland in Gilan, Iran. The aim was to investigate the suitability of magnetic properties measurements for indicating heavy metal pollution. The concentration of six heavy metals (Ni, Cr, Cd, Zn, Fe, and Pb) was determined in different depths of four sediment core samples within four different regions of the wetland (Abkenar, Hendekhaleh, Shijan and Siakeshim). Average concentration of heavy metals in the sediment cores was higher than the severe effect level (SEL) for Ni, Cr and Fe (77.26, 113.63 ppm and 5.2%, respectively) and lower than SEL for Cd, Zn and Pb (0.84, 137.7, 29.77 ppm, respectively). It was found that the trend of metal concentrations with the depth is different in each core and is related to the pollution discharges into the rivers entering the wetland. Core magnetic susceptibility measurements also showed different magnetic properties in each core. Cluster analysis was applied using Pearson correlation coefficient between heavy metal concentrations and magnetic properties across each core. Significant relationship was found to exist between magnetic susceptibility and the concentration of Ni in Abkenar and the concentration of Fe in other regions. Whereas Abkenar is almost the isolated and uncontaminated region of the wetland, it revealed a difference in magnetic properties between contaminated and uncontaminated sediments. It was concluded that magnetic properties of samples from contaminated zone were mostly related to Fe content. The result of this study demonstrated that magnetic susceptibility measurements could be applied as a proxy method for heavy metal pollution determination in marine environments in Iran especially as a rapid and cost-effective introductory site assessments.


Unintended impacts of a Medicaid prior authorization policy on access to medications for bipolar illness.
Prior authorization policies (PA) are widely used to control psychotropic medication costs by state Medicaid programs and Medicare Part D plans. The objective of this study was to examine the impact of a Maine Medicaid PA policy on initiation and switching of anticonvulsant and atypical antipsychotic treatments among patients with bipolar disorder. We obtained Maine and New Hampshire (comparison state) Medicaid and Medicare claims data for 2001 to 2004; the Maine PA policy was implemented in July 2003. Among continuously enrolled patients with bipolar disorder (Maine: n = 5336; New Hampshire: n = 1376), we used an interrupted times series with comparison group design to estimate changes in rates of initiating new episodes of bipolar treatment and generalized estimating equations models to examine rates of switching therapies among patients under treatment. The Maine PA policy was associated with a marked decrease in rates of initiation of bipolar treatments; a relative reduction of 32.3% (95% CI: 24.8, 39.9) compared with expected rates at 4 months after policy implementation. This decrease was driven primarily by reductions in the initiation of nonpreferred agents. The policy had no discernable impact on rates of switching therapy among patients currently on treatment (RR: 1.03; 95% CI: 0.76, 1.39). The findings of this study provide evidence that PA implementation can be a barrier to initiation of nonpreferred agents without offsetting increases in initiation of preferred agents, which is a major concern. There is a critical need to evaluate the possible unintended effects of PA policies to achieve optimal health outcomes among low-income patients with chronic mental illness. In addition, more research is needed to understand how these barriers arise and whether specific seriously mentally ill populations or drug classes should be exempted from PA policies.


Enhanced rare earth photoluminescence in inverse opal photonic crystals and its application for pH sensing.
Concentration quenching effects of identical rare earth (RE) activator ions and energy transfer (ET) between different RE ions often compromise the photoluminescence (PL) quantum efficiency in RE based luminescence materials. Here, we demonstrate that in NaGd(WO4)2:Tb(3+), Eu(3+) inverse opal photonic crystals (IOPCs), the suppression of the emission line located in the photonic stop band (PSB) and a dramatic increase of the lifetimes of Eu(3+) and Tb(3+) ions are observed. More interestingly, the concentration quenching among Eu(3+) ions and ET from Tb(3+) to Eu(3+) is significantly relieved owing to the periodic empty cavity structure of IOPCs. As a consequence, the luminescent quantum efficiency (QE) of the NaGd(WO4)2:Tb(3+), Eu(3+) IOPCs increases ∼2 times more than that of crushed NaGd(WO4)2:Tb(3+), Eu(3+) powder. In addition, a reusable pH sensor with good linear response (pH 5-10) has been designed based on the high surface-to-volume ratio, high connectivity, and enhanced luminescence of NaGd(WO4)2:Tb(3+), Eu(3+)IOPCs, which could be applied to the dynamical detection of pH value.


Characteristics of annual exposure to noise among private farmers on family farms of mixed-production profile.
The objective of the study was the recognition and evaluation of annual exposure to noise among private farmers on farms engaged in mixed (plant-animal) production. The study covered 16 family farms using land of the size 13-30 ha (20.4 ha on average). The farms were equipped with agricultural tractors (2.4 tractors on average), selected workshop machinery, saws for logging and machines for the production of fodder. The following basic parameters were applied for the hygienic evaluation of noise: total monthly exposure and mean equivalent daily exposure expressed in Pa2 h. The study indicated that the highest values for total monthly exposure to noise were observed in 5 months, i.e. September, October, August, November and April. High total exposure values obtained in the summer-autumn months (August-November) are associated with the performance of such work activities as: harvesting of cereals and root plants, and cultivation of soil (characterised by the emission of sounds of high levels), with prolonged exposure to this factor and a large number of workdays in these months. In April, however, the occurrence of high total exposure values was due to intensive field activities (ploughing, harrowing, sowing), and prolonged exposure to this factor. In the seasons of the year analysed, high equivalent exposure values were observed within the range: 5.53-6.61 Pa2 h. Mean value for this parameter for the whole year reached the value of 4.27 Pa(2) h (standard exceeded 4.3 times). This value is equivalent to a mean exposure level equal to 91.3 dB. The results of studies of annual exposure to noise obtained by some other authors are close to the data presented in this report, and confirm that the degree of noise load clearly depends on the type of agricultural production and type of machines applied.


Enzyme-linked amperometric electrochemical genosensor assay for the detection of PCR amplicons on a streptavidin-treated screen-printed carbon electrode.
A general purpose enzyme-based amperometric electrochemical genosensor assay was developed wherein polymerase chain reaction (PCR) amplicons labeled with both biotin and fluorescein were detected with peroxidase-conjugated antifluorescein antibody on a screen-printed carbon electrode (SPCE). As a proof of principle, the response selectivity of the genosensor was evaluated using PCR amplicons derived from lolB gene of Vibrio cholerae. Factors affecting immobilization, hybridization, and nonspecific binding were optimized to maximize sensitivity and reduce assay time. On the basis of the background amperometry signals obtained from nonspecific organisms and positive signals obtained from known V. cholerae, a threshold point of 4.20 microA signal was determined as positive. Under the optimum conditions, the limit of detection (LOD) of the assay was 10 CFU/mL of V. cholerae. The overall precision of this assay was good, with the coefficient of variation (CV) being 3.7% using SPCE and intermittent pulse amperometry (IPA) as an electrochemical technique. The assay is sensitive, safe, and cost-effective when compared to conventional agarose gel electrophoresis, real-time PCR, and other enzyme-linked assays for the detection of PCR amplicons. Furthermore, the use of a hand-held portable reader makes it suitable for use in the field.


Methods for microelectrode-guided posteroventral pallidotomy.
Methods for localizing the posteroventral globus pallidus intermus are described. The authors' techniques include the use of microelectrodes to record single-unit activity and to microstimulate in human pallidum and its surrounding structures. This technique allows a precise determination of the locations of characteristic cell types in sequential trajectories through the external and internal segments of the pallidum. The location of the optic tract can be determined from microstimulation-evoked visual sensations and recordings of flash-evoked potentials. In addition, microstimulation-evoked motor and sensory responses allow the internal capsule to be identified. The data collected using this technique are an important adjunct to selecting optimum sites to place electrocoagulation lesions for stereotactic posteroventral pallidotomy for refractory Parkinson's disease.


[Hypermyoglobinemia and creatine phosphokinase MB activity as signs of combined myocardial lesion and acute cerebral circulatory disorder].
In order to detect simultaneous damage to the myocardium in cerebral stroke the authors radioimmunoassayed myoglubin and activity of the heart fraction of creatine phosphokinase MB (CP K MB) in the blood serum of 22 patients. Hypermyoglobinemia and elevated activity of CP K MB were revealed in almost all cases of hemorrhagic stroke (15 patients) whereas in patients with ischemic stroke they were identified far less frequently. Thus, hypermyoglobinemia and the activity of CP K MB correlate with the macro- and microscopic picture of myocardial damage and may serve as its diagnostic criteria when both the clinical picture and ECG findings prove uninformative.


Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer-More is Better? A Large International Population-based Cohort Study.
This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [ORSEER-18 = 1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.


Calcified neurocysticercosis lesions trigger symptomatic inflammation during antiparasitic therapy.
We report a patient with neurocysticercosis who developed numerous cerebral edematous lesions while undergoing cysticidal therapy. These lesions outnumbered viable cystic lesions seen before therapy. Most new lesions were subsequently found to be associated with former calcifications not seen on initial MR imaging. Calcified neurocysticercosis lesions can trigger inflammatory reactions during therapy, and the number and location of calcified neurocysticercosis lesions may influence treatment decisions.


Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus.
LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which significantly decreased let-7 miRNAs and increased IGF2BP1-3, HMGA1, ARID3B, and c-MYC compared to control. This is the first study showing the role of the LIN28-let-7 axis in trophoblast proliferation and conceptus elongation in vivo. These results suggest that reduced LIN28 during early placental development can lead to reduced trophoblast proliferation and sheep conceptus elongation at a critical period for successful establishment of pregnancy.


Mediators and moderators of nutrition intervention effects in remote Indigenous Australia.
We conducted a longitudinal dietary intervention study to assess the impact of a store-based intervention on mediators and moderators and consequent dietary behaviour in Indigenous communities in remote Australia. We assessed dietary intake of fruit, vegetable, water and sweetened soft drink, mediators and moderators among 148, eighty-five and seventy-three adult participants (92 % women) at baseline (T1), end of intervention (T2) and at 24 weeks post intervention (T3), respectively. Mediators included perceived affordability and self-efficacy. Moderators were barriers to eat more fruit and vegetables and food security. Mixed-effects models were used to determine changes in mediators and moderators with time and associations between these and each dietary outcome. Perceived vegetable affordability increased from T1 (19 %; 95 % CI 11, 27) to T2 (38 %; 95 % CI 25, 51) (P=0·004) and returned to baseline levels at T3. High self-efficacy to eat more fruit and vegetables and to drink less soft drink decreased from T1 to T3. A reduction in soft drink intake of 27 % (95 % CI -44, -4; P=0·02) was reported at T3 compared with T1; no changes with time were observed for all other outcome measures. Regardless of time, vegetable intake was positively associated with self-efficacy to cook and try new vegetables, no barriers and food security. The dietary intervention went someway to improving perceived affordability of vegetables but was probably not strong enough to overcome other mediators and moderators constraining behaviour change. Meaningful dietary improvement in this context will be difficult to achieve without addressing underlying constraints to behaviour change.


Clinical and therapeutic properties of Cushing's disease in childhood.
Cushing's disease (CD) in adolescence and childhood is a rare pathology and has some different clinical and therapeutic characteristics than in adults. We report 3 cases treated surgically, with the diagnosis of CD. Their common complaints were short stature and obesity. Endocrinological investigations and radiological evaluation pointed out the diagnosis of CD for all children. They were operated on by the transsphenoidal route, and adenoma resection was performed. Histopathologic and immunohistochemical examination of the tissue specimens confirmed the diagnosis of CD. Long-term follow-up demonstrated weight loss and increase in height.


Phylogeny of Bacillus sphaericus-like organisms.
The mesophilic round-spored bacteria embrace four species, namely Bacillus sphaericus, Bacillus fusiformis, Bacillus silvestris and Bacillus pasteurii. Although not displayed by all strains, mosquito pathogenicity is a noteworthy characteristic of B. sphaericus sensu lato. Phylogenetic analysis based on 16S rDNA sequences from 58 strains identified as B. sphaericus was used to examine the genetic heterogeneity of the taxon. Results from sequence analysis were compared with whole-cell fatty acid profiles and other phenotypic determinations. The B. sphaericus-like strains segregated into seven distinct clusters in a phylogenetic tree generated from 16S sequences. One cluster represented B. sphaericus and another B. fusiformis. A third cluster containing all of the pathogenic strains was closely related to, or was possibly part of, the B. fusiformis group. The remaining four groups were distinct and represented unnamed taxa that were more closely related to B. sphaericus and B. fusiformis than to the psychrophilic round-spored species, Bacillus globisporus and Bacillus psychrophilus. Groups based on phenotypic analysis corresponded to the 16S rDNA phylogenetic clusters. Data showed that B. sphaericus was genetically and phenotypically a highly heterogeneous taxon including at least seven genetically distinct taxa. The pathogenic strains were members of a distinct group and not of the species B. sphaericus sensu stricto. This heterogeneity partially accounts for the apparent variability of mosquito pathogenicity among B. sphaericus strains.


Succinylation of hapten-protein conjugates facilitates coupling to erythrocytes by water soluble carbodiimide: preparation of stable and sensitive target cells for use in hemolytic assays.
A facile method is described for the preparation of haptenated sheep red blood cells (SRBC) for use as targets in hemolytic spot and plaque assays for the detection of anti-hapten antibody. The method involves the use of the water soluble 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDCI) as a reagent to couple hapten-succinyl-rabbit serum albumin conjugates to SRBC. The presence of the succinyl groups on such conjugates is shown to increase the efficacy of the resulting target cells, presumably by acting as a substrate for the EDCI and thus increasing the extent of coupling to SRBC.


Effect of pacing-induced myocardial ischemia on platelet activation and fibrin formation in the coronary circulation.
The effect of pacing-induced myocardial ischemia on platelet activation and fibrin formation was investigated in seven patients with severe proximal lesions of the left anterior descending coronary artery to determine if acute ischemia activates the coagulation system. Fibrin formation was assessed from plasma levels of fibrinopeptide A. Platelet activation was assessed by levels of platelet factor 4, beta-thromboglobulin and thromboxane B2. Plasma levels were measured before, during and after acute myocardial ischemia induced by rapid atrial pacing. Blood samples were collected from the ascending aorta and from the great cardiac vein through heparin-bonded catheters. The occurrence of anterior myocardial ischemia was established by electrocardiography and by myocardial lactate extraction. No significant transmyocardial gradients in the levels of fibrinopeptide A, platelet factor 4, beta-thromboglobulin or thromboxane B2 were found at rest, during ischemia or in the recovery period, and levels in the great cardiac vein did not change in response to ischemia. These data indicate that pacing-induced myocardial ischemia does not result in release of fibrinopeptide A, platelet factor 4, beta-thromboglobulin or thromboxane B2 into the coronary circulation, and imply that acute ischemia does not induce platelet activation or fibrin formation in the coronary circulation.


Spatial Difference of Transit-Based Accessibility to Hospitals by Regions Using Spatially Adjusted ANOVA.
This paper proposes a spatial difference analysis method for evaluating transit-based accessibility to hospitals using spatially adjusted ANOVA. This method specializes in examining spatial variations of accessibility to hospitals by regions (i.e. administrative districts or subdistricts). The spatial lag model is applied to adjust traditional ANOVA, which reduces spatial dependency and avoids false rejection to null hypothesis. Multiple comparison methods are used for further detection of differences in accessibility between regions. After multiple comparison, accessibility within regions is classified into three levels. The study is conducted on two scales-administrative districts and subdistricts-to discuss spatial variations in macro and micro dimensions respectively in the central part of Wuhan, China. Accessibility is calculated by using a simple model and a gravity model. The final classification results showed that the spatially adjusted method is more reliable than the traditional non spatially adjusted one and the gravity model can better detect more hidden information about the inequal distribution of medical resources. It is also found that the subdistricts, which have significantly lower accessibility to hospitals than others, are mainly distributed in Hongshan and Qingshan district. Our study hopes to shed new lights in spatial difference analysis for accessibility and provide policy recommendations that would promote equality in provisions of public health services.


Use of Temporary Mechanical Circulatory Support for Management of Cardiogenic Shock Before and After the United Network for Organ Sharing Donor Heart Allocation System Changes.
The new United Network for Organ Sharing (UNOS) donor heart allocation system gives priority to patients supported with nondischargeable mechanical circulatory support (MCS) devices while awaiting heart transplant. Whether there has been a change in temporary MCS use in cardiac intensive care units (CICUs) since the implementation of this policy is unknown. To examine whether the UNOS donor heart allocation system revision in October 2018 was associated with changes in temporary MCS use in CICUs and whether temporary MCS use differed between US transplant centers and US nontransplant centers and Canadian centers. In this cohort study, 14 centers from the Critical Care Cardiology Trials Network (CCCTN), a multicenter network of tertiary CICUs in North America, contributed 2-month snapshots of consecutive medical CICU admissions between September 1, 2017, and September 1, 2018 (prerevision period), and October 1, 2018, and September 1, 2019 (postrevision period). CICUs were classified as US transplant centers (n = 7) or other CICUs (US nontransplant centers or Canadian centers; n = 7). Revision to the UNOS donor heart allocation system. Treatment with temporary MCS (intra-aortic balloon pump, microaxial intracardiac ventricular assist device, percutaneous centrifugal ventricular assist device, venoarterial extracorporeal membrane oxygenation, or surgically implanted, nondischargeable MCS device) during hospital admission. A total of 384 admissions for acute, decompensated, heart failure-related cardiogenic shock (ADHF-CS) were included, among which 248 (64.6%) were to US transplant centers; 126 admissions (51%) were in the prerevision period and 122 (49%) were in the postrevision period. The mean (SD) patient age was 61.2 (14.6) years; 246 patients (64.1%) were male. The proportion of admissions with ADHF-CS managed with temporary MCS at US transplant centers significantly increased from 25.4% (32 of 126 admissions) before to 42.6% (52 of 122 admissions) after the UNOS allocation system changes (P = .004). In other CICUs, the proportion did not significantly change (24.5% [13 of 53 admissions] to 24.1% [20 of 83 admissions]; P = .95). After multivariable adjustment, patients admitted to US transplant centers in the postrevision period were more likely to receive temporary MCS compared with those admitted in the prerevision period (adjusted odds ratio, 2.19; 95% CI, 1.13-4.24; P = .02). In the year after implementation of the new UNOS donor heart allocation system, temporary MCS use in patients admitted with ADHF-CS increased in US transplant centers but not in other CICUs. Whether this shift in practice will affect outcomes of patients with ADHF-CS or organ distribution should be evaluated.


Understanding Geographic Variation in Systemic Overuse Among the Privately Insured.
Medical care overuse is a significant source of patient harm and wasteful spending. Understanding the drivers of overuse is essential to the design of effective interventions. We tested the association between structural factors of the health care delivery system and regional differences systemic overuse. We conducted a retrospective analysis of deidentified claims for 18- to 64-year-old adults from the IBM MarketScan Commercial Claims and Encounters Database. We calculated a semiannual Johns Hopkins Overuse Index for each of the 375 Metropolitan Statistical Areas in the United States, from January 2011 to June 2015. We fit an ordinary least squares regression to model the Johns Hopkins Overuse Index as a function of regional characteristics of the health care system, adjusted for confounders and time. The supply of regional health care resources was associated with systemic overuse in commercially insured beneficiaries. Regional characteristics associated with systemic overuse included number of physicians per 1000 residents (P=0.001) and higher Medicare malpractice geographic price cost index (P<0.001). Regions with a higher density of primary care physicians (P=0.008) and a higher proportion of hospital-based providers (P=0.016) had less systemic overuse. Differences in hospital and insurer market power were inversely associated with systemic overuse. Systemic overuse is associated with observable, structural characteristics of the regional health care system. These findings suggest that interventions that aim to improve care efficiency via reductions in overuse should focus on the structural drivers of this phenomenon, rather than on the eradication of individual overused procedures.


Adherence and autoaggregation phenotypes of a Burkholderia cenocepacia cable pilus mutant.
Cable pili are unique peritrichous adherence organelles expressed by certain strains of the opportunistic human pathogen Burkholderia cenocepacia. Cable pili have been proposed to facilitate binding to human epithelial cells and mucin, and may play a role in the ability of B. cenocepacia to colonise the respiratory tract of compromised hosts. In this study, a genetic approach was undertaken to assess the role of cable pili in mediating adherence as well as bacterial cell-cell interactions. The cblA gene, encoding the major pilin subunit, was insertionally inactivated, and the resulting mutant was shown to be blocked in CblA expression and in cable pilus morphogenesis. Although non-piliated, the cblA mutant was not defective in adherence to either porcine mucin or to cultured A549 human respiratory epithelial cells. Microscopic and flow cytometric analyses of B. cenocepacia cultures revealed that cable pilus expression facilitated the formation of diffuse cell networks, whereas disruption of cable pilus biogenesis enhanced autoaggregation and the formation of compact cell aggregates. Autoaggregation was observed both in culture and during B. cenocepacia infection of A549 epithelial cell monolayers. These findings indicate that cable pilus expression plays an important role in mediating B. cenocepacia cell-cell interactions, and that both cable pilus-dependent and cable pilus-independent mechanisms may contribute to B. cenocepacia adherence to cellular and acellular surfaces.


Efficacy and safety of 7 days versus 10 days triple therapy based on levofloxacin-dexlansoprazole for eradication of Helicobacter pylori: A pilot randomized trial.
Levofloxacin-based triple therapies are considered the standard regimen for eradication of Helicobacter pylori (H. pylori) due to decreased sensitivity to clarithromycin and the optimal duration of therapy is still controversial. Besides, there is no complete evidence about dexlansoprazole efficacy in the eradication of H. pylori. Our study aimed to determine the effectiveness of triple therapy based on levofloxacin-dexlansoprazole as a standard treatment for H. pylori infection and estimate the effect of H. pylori on lipid profile and hemoglobin (Hb). A pilot prospective randomized trial of a triple therapy based on levofloxacin-dexlansoprazole for H. pylori eradication was conducted at Damanhour Medical National Institute, Egypt; 66 participants with H. pylori infection received levofloxacin (500 mg/day) plus amoxicillin (1 g/12 h) plus dexlansoprazole (60 mg/day). All medications administrated orally for either 7 days or 10 days. Four weeks after treatment, the eradication was assessed by the stool antigen test. The rate of eradication was 63.6% in levofloxacin, amoxicillin, and dexlansoprazole (LAD) 7-day group, and 90.9% in LAD 10-day group. In addition, laboratory test results showed a significant difference in Hb, low-density lipoprotein, high-density lipoprotein, triglyceride, and total cholesterol levels before and after treatment (P < 0.05). LAD 10 days is the least duration that provides maximum efficacy for H. pylori in Egyptian participants. In addition, successful treatment of H. pylori infection may reduce the risk of anemia and dyslipidemia. Furthermore, all members of the patient's family should be screened for H. pylori to prevent recurrent infection.


Genes and membrane signals involved in neoplastic transformation.
Figure 2 summarizes our current understanding of the signal transduction events that appear to be involved in promotion of transformation in JB6 cells. Among the earliest promotion-relevant events (at least for phorbol esters) appear to be C-kinase activation and superoxide anion elevation. Whether such events regulate expression of pro genes needs to be elucidated. Finally, Fig. 3 presents a model for the role of pro genes and transforming genes in inducing and maintaining neoplastic transformation in mouse JB6 cells. Our current hypothesis is that TPA interacts with its receptor (C-kinase) to trigger one or more promotion-relevant second messages, which then activate expression of pro gene(s). The product of a pro gene is postulated to then activate expression of a transforming gene so that its expression becomes constitutive in the neoplastic cell. In the P- cells the "defect" could be at the level of a missing second messenger signal to activate pro genes or a structural change in pro genes such that they are not expressed or they lack activity even though expressed. Recent evidence to be presented elsewhere indicates that pro genes are not limited to mouse cells but are found in certain human tumor and nontumor cells. If human pro homologues turn out to show biological activity for specifying sensitivity to neoplastic transformation, this finding will add a new dimension to testing the somatic mutation hypothesis of carcinogenesis.


Spontaneous progression of cutaneous angiomatosis to an infiltrative sarcoma-like tumour in a bull.
A 5-month-old valuable Red Holstein bull presented with a cutaneous mass on the fetlock of the right hind limb. The mass was removed and histologically diagnosed as a benign angiomatosis. Four months later, the mass reoccurred on the same leg. The first excision biopsy consisted of numerous blood vessels of different diameters and wall thicknesses. Often, the smaller vessels were oriented around a larger, vein-like vessel. The endothelial cells were elongated with small oval to elongated nuclei with dense chromatin. Following recurrence, the mass showed clear signs of infiltrative growth, including solid bundles of cells, increased polymorphism and round to oval nuclei with coarse chromatin and distinctive nucleoli. The neoplastic cells were immunohistochemically positive for von Willebrand Factor (vWF). Angiomatosis with focal progression to an infiltrative growing sarcoma-like tumour. This case represents the progression of a benign vascular proliferation, often considered as a reactive process, into a more aggressively behaving neoplasm. The clinical behaviour and histopathological morphology were strikingly similar to previous cases described in human and veterinary medicine.


Low levels of B-type natriuretic peptide predict poor clinical outcomes in patients with chronic and advanced heart failure.
B-type natriuretic peptide (BNP) is a neurohormone produced mainly by ventricular myocytes in response to increased left ventricular end-diastolic pressure. Patients with acute decompensated heart failure often have elevated plasma BNP. However, recent clinical observations have demonstrated that in patients with advanced heart failure, the plasma level of BNP is lower than those with acute heart failure. We hypothesized that a lower circulating BNP level in patients with chronic and advanced heart failure is due to the exhaustion of the biosynthesis mechanisms and is associated with a poor outcome in these patients.


Improving access to emergency contraception pills through strengthening service delivery and demand generation: a systematic review of current evidence in low and middle-income countries.
Emergency contraception pills (ECP) are among the 13 essential commodities in the framework for action established by the UN Commission on Life-Saving Commodities for Women and Children. Despite having been on the market for nearly 20 years, a number of barriers still limit women's access to ECP in low- and middle-income countries (LMIC) including limited consumer knowledge and poor availability. This paper reports the results of a review to synthesise the current evidence on service delivery strategies to improve access to ECP. A narrative synthesis methodology was used to examine peer reviewed research literature (2003 to 2013) from diverse methodological traditions to provide critical insights into strategies to improve access from a service delivery perspective. The studies were appraised using established scoring systems and the findings of included papers thematically analysed and patterns mapped across all findings using concept mapping. Ten papers were included in the review. Despite limited research of adequate quality, promising strategies to improve access were identified including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m-health for information provision; and scale up through national family planning programs. There are a number of gaps in the research concerning service delivery and ECP in LMIC. These include a lack of knowledge concerning private/commercial sector contributions to improving access, the needs of vulnerable groups of women, approaches to enhancing intersectoral collaboration, evidence for social marketing models and investment cases for ECP.


The energetic and carbon economic origins of leaf thermoregulation.
Leaf thermoregulation has been documented in a handful of studies, but the generality and origins of this pattern are unclear. We suggest that leaf thermoregulation is widespread in both space and time, and originates from the optimization of leaf traits to maximize leaf carbon gain across and within variable environments. Here we use global data for leaf temperatures, traits and photosynthesis to evaluate predictions from a novel theory of thermoregulation that synthesizes energy budget and carbon economics theories. Our results reveal that variation in leaf temperatures and physiological performance are tightly linked to leaf traits and carbon economics. The theory, parameterized with global averaged leaf traits and microclimate, predicts a moderate level of leaf thermoregulation across a broad air temperature gradient. These predictions are supported by independent data for diverse taxa spanning a global air temperature range of ∼60 °C. Moreover, our theory predicts that net carbon assimilation can be maximized by means of a trade-off between leaf thermal stability and photosynthetic stability. This prediction is supported by globally distributed data for leaf thermal and photosynthetic traits. Our results demonstrate that the temperatures of plant tissues, and not just air, are vital to developing more accurate Earth system models.


Gestational exposure to cannabidiol leads to glucose intolerance in 3-month-old male offspring.
Reports in North America suggest that up to 20% of young women (18-24 years) use cannabis during pregnancy. This is concerning given clinical studies indicate that maternal cannabis use is associated with fetal growth restriction and dysglycemia in the offspring. Preclinical studies demonstrated that prenatal exposure to Δ9-tetrahydrocannabinol, the main psychoactive component of cannabis, in rat dams led to female-specific deficits in β-cell mass and glucose intolerance/insulin resistance. Yet to date, the contributions of cannabidiol (CBD), the primary nonpsychoactive compound in cannabis, remain elusive. This study aimed to define the effects of in utero cannabidiol (CBD) exposure on postnatal glucose regulation. Pregnant Wistar rat dams received daily intraperitoneal injections of either a vehicle solution or 3 mg/kg of CBD from gestational day (GD) 6 to parturition. CBD exposure did not lead to observable changes in maternal or neonatal outcomes; however, by 3 months of age male CBD-exposed offspring exhibited glucose intolerance despite no changes in pancreatic β/α-cell mass. Transcriptomic analysis on the livers of these CBD-exposed males revealed altered gene expression of circadian rhythm clock machinery, which is linked to systemic glucose intolerance. Furthermore, alterations in hepatic developmental and metabolic processes were also observed, suggesting gestational CBD exposure has a long-lasting detrimental effect on liver health throughout life. Collectively, these results indicate that exposure to CBD alone in pregnancy may be detrimental to the metabolic health of the offspring later in life.


Prevention of choking, strangulation, and suffocation in childhood.
Choking, suffocation and strangulation are important causes of unintentional injury and death in young children. Choking on food and toys, suffocation from plastic bags and strangulation from strings on children's items are common causes of mechanical airway obstruction. An effective prevention plan must include education, product labeling, and product and container modification. Health care providers can play an important role in the dissemination of prevention information to caregivers and manufacturers in order to reduce the incidence of these injuries in young children. In the United States, mechanical airway obstruction from choking, suffocation and strangulation is the leading cause of unintentional injury that results in death of children less than 1 year. It ranks fourth as a cause of death in children 1 to 9 years, surpassed only by motor vehicle injuries, drowning/submersion, and fire/burns. Many of these deaths are preventable. Prevention of death from mechanical airway obstruction has long been a concern of health care providers, whose role may involve education of parents, other caregivers and manufacturers about the risks and the prevention of choking, suffocation and strangulation in children. Choking is the interruption of respiration by internal obstruction of the airway, usually by food or small toys in young children. Suffocation is obstruction of the airway from an external object that blocks the nose and mouth, such as a plastic bag. Strangulation also results from external compression of the airway from an object, such as a string that becomes caught around the neck.


The risks and benefits of using social media to engage consumers in service design and quality improvement in Australian public hospitals: findings from an interview study of key stakeholders.
Engaging consumers - patients, families, carers and community members who are current or potential service users - in the planning, design, delivery, and improvement of health services is a requirement of public hospital accreditation in Australia. There is evidence of social media being used for consumer engagement in hospitals internationally, but in Australia this use is uncommon and stakeholders' experiences have not been investigated. The aim of the study was to explore the experiences and beliefs of key Australian public hospital stakeholders around using social media as a consumer engagement tool. This article focuses on the study findings relating to methods, risks, and benefits of social media use. Semi-structured interviews were conducted with Australian public hospital stakeholders in consumer representative, consumer engagement/patient experience, communications or quality improvement roles. Qualitative data were analysed using a deductive content analysis method. An advisory committee of consumer and service provider stakeholders provided input into the design and conduct of this study. Twenty-six Australian public hospital service providers and consumers were interviewed. Participants described social media being used to: recruit consumers for service design and quality improvement activities; as an online space to conduct consultations or co-design; and, to gather feedback and patient experience data. The risks and benefits discussed by interview participants were grouped into five themes: 1) overcoming barriers to engagement, 2) consumer-initiated engagement; 3) breadth vs depth of engagement, 4) organisational transparency vs control and 5) users causing harm. Social media can be used to facilitate consumer engagement in hospital service design and quality improvement. However, social media alone is unlikely to solve broader issues commonly experienced within health consumer engagement activities, such as tokenistic engagement methods, and lack of clear processes for integrating consumer and patient feedback into quality improvement activities.


[Characterization of Schizosaccharomyces hominis].
The cultural, morphological, physiological and biological characteristics of Schizosaccharomyces hominis, Benedek strain BKM Y-650 were under study. This name is regarded as synonymous to Schizosaccharomyces pombe Lindner.


Pressure-induced phases of sulfur.
At least three phases of sulfur may be induced at pressures between 16 and 65 kilobars. A fibrous form obtained at pressures of 27 kilobars and higher appears to be closely related to the form obtained when plastic sulfur is chilled and stretched. Crystals of the fibrous form are orthorhombic with a = 13.8, b = 32.4, and c = 9.25 A. Thus far the results are in accord with deductions made by Prins and co-workers that the sulfur atoms are arranged in helices with ten atoms and three turns per 13.8-A period, and that these helices are essentially close-packed. The unit cell contains 16 ten-atom chain lengths. The probable space groups to which the crystal may belong are C c m m, C c 2 m, or C c m 2(1). These imply that the structure must contain both right- and left-handed helices and that at least half the helices have some disorder about their axes. The other two phases appear to have structures related to that of the fibrous form, but analyses of them has not progressed as far. One of these phases appears to be uomegasulfur.


Current research in coitus-induced ovulation: a review.
Against the background of renewed interest in the existence of reflex ovulation in many animal species and the possibility of its existence in man, this review on current research efforts embraces the multitude of nervous influences and stimuli accompanying cohabitation. Species showing reflex ovulation are not restricted to those using this as the sole ovulatory mechanism, but include also so-called facultative ovulators, which seem to use this mechanism as a last resort to assure reproductive capacity under adverse situations (rat); and species which for the length of the standing heat period become temporarily induced ovulators for the optimal coordination of all necessary steps to assure fertility (cattle, pig, sheep); and species in which frequent cohabitation (rat) or a single coitus after artificial insemination (sheep) assures either optimal ovulation or conception rates. Copulation might not always be essential; some of the cohabitation-related reflexes might be transmitted by olfactory, ocular, tactile and acoustic stimuli; emotions may play a role. These stimuli are transmitted to the CNS from the periphery by afferent nervous pathways, and are translated in the thalamic-hypothalamic-pituitary complex into neurohormonal phenomena, causing ovulation; or may cause, mainly by LH and/or oxytocin discharge, an acceleration or augmentation of processes involved in spontaneous ovulation. Intensive biochemical and pharmacological studies have unveiled some of the neurohormonal mechanisms involved in the hypothalamus and how these stimuli are transmitted to the pituitary or received at the ovarian level, as hormonal or neurohormonal phenomena.


Cardiac arrhythmia is the primary response of embryonic Pacific herring (Clupea pallasi) exposed to crude oil during weathering.
Teleost embryos develop a syndrome characterized by edema when exposed to water that weathers substrates contaminated with crude oil. Previous studies using zebrafish demonstrated that crude oil exposure causes cardiogenic edema, and that the most abundant polycyclic aromatic hydrocarbons (PAHs) in weathered crude oils (tricyclic fluorenes, dibenzothiophenes, and phenanthrenes) are cardiotoxic, causing arrhythmia through a pathway that does not require activation of the aryl hydrocarbon receptor (AHR). We demonstrate here for Pacific herring, a species impacted by the Exxon Valdez oil spill, that the developing heart is the primary target of crude oil exposure. Herring embryos exposed to the effluent of oiled gravel columns developed dose-dependent edema and irregular cardiac arrhythmia soon afterthe heartbeat was established. At a dose that produced cardiac dysfunction in 100% of exposed embryos, tissue levels of tricyclic PAHs were below 1 micromol/kg, suggesting a specific, high affinity target in the heart. These findings have implications for understanding the mechanism of tricyclic PAH cardiotoxicity, the development of biomarkers for the effects of PAH exposure in fish, and understanding the long-term impacts of oil spills and other sources of PAH pollution in aquatic environments.


Oxytocin's anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1β and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.


Bacterial Tomato Pathogen Ralstonia solanacearum Invasion Modulates Rhizosphere Compounds and Facilitates the Cascade Effect of Fungal Pathogen Fusarium solani.
Soil-borne pathogen invasions can significantly change the microbial communities of the host rhizosphere. However, whether bacterial Ralstonia solanacearum pathogen invasion influences the abundance of fungal pathogens remains unclear. In this study, we combined high-throughput sequencing, qPCR, liquid chromatography and soil culture experiments to analyze the rhizosphere fungal composition, co-occurrence of fungal communities, copy numbers of functional genes, contents of phenolic acids and their associations in healthy and bacterial wilt-diseased tomato plants. We found that R. solanacearum invasion increased the abundance of the soil-borne pathogen Fusarium solani. The concentrations of three phenolic acids in the rhizosphere soil of bacterial wilt-diseased tomato plants were significantly higher than those in the rhizosphere soil of healthy tomato plants. In addition, the increased concentrations of phenolic acids significantly stimulated F. solani growth in the soil. Furthermore, a simple fungal network with fewer links, nodes and hubs (highly connected nodes) was found in the diseased tomato plant rhizosphere. These results indicate that once the symptom of bacterial wilt disease is observed in tomato, the roots of the wilt-diseased tomato plants need to be removed in a timely manner to prevent the enrichment of other fungal soil-borne pathogens. These findings provide some ecological clues for the mixed co-occurrence of bacterial wilt disease and other fungal soil-borne diseases.


Sonographic evaluation of thyroid morphology during the normal estrous cycle in the Indo-Pacific bottlenose dolphin (Tursiops aduncus).
Physiologic changes occurring in the thyroid in response to the estrous cycle have been noted in companion animals. However, in bottlenose dolphins, the influence of different reproductive states on thyroid morphology remains unclear. Sonography was used to evaluate the variations of thyroid morphology for nine consecutive estrous cycles of four sexually mature, female Indo-Pacific bottlenose dolphins (Tursiops aduncus). The estrous cycle was divided into two phases for evaluation: the follicular and luteal phases. To compare changes associated with sex, thyroid volumes were measured in the different phases during the estrous cycle of female dolphins and were compared to the ultrasound examinations of the four male dolphins measured over a 2-mo period. In males, there was no significant difference in thyroid volume during the study period (P > 0.05). The thyroid volume measured in combining all estrous cycle phases of the female dolphins was significantly larger than that measured in the male dolphins (P < 0.05). A difference in thyroid volume during the estrous cycle was observed, with the thyroid volume during the follicular phase significantly smaller (P < 0.05) than that of the luteal phase, and is possibly related to the influence of female sex steroids. Thyroid volume variability during estrus should, therefore, be taken into account when examining the thyroid gland of female dolphins.


Antiviral, Cytoprotective, and Anti-Inflammatory Effect of Ampelozizyphus amazonicus Ducke Ethanolic Wood Extract on Chikungunya Virus Infection.
Chikungunya fever, a debilitating disease caused by Chikungunya virus (CHIKV), is characterized by a high fever of sudden onset and an intense arthralgia that impairs individual regular activities. Although most symptoms are self-limited, long-term persistent arthralgia is observed in 30-40% of infected individuals. Currently, there is no vaccine or specific treatment against CHIKV infection, so there is an urgent need for the discovery of new therapeutic options for CHIKF chronic cases. This present study aims to test the antiviral, cytoprotective, and anti-inflammatory activities of an ethanol extract (FF72) from Ampelozizyphus amazonicus Ducke wood, chemically characterized using mass spectrometry, which indicated the major presence of dammarane-type triterpenoid saponins. The major saponin in the extract, with a deprotonated molecule ion m/z 897 [M-H]-, was tentatively assigned as a jujubogenin triglycoside, a dammarane-type triterpenoid saponin. Treatment with FF72 resulted in a significant reduction in both virus replication and the production of infective virions in BHK-21-infected cells. The viability of infected cells was assessed using an MTT, and the result indicated that FF72 treatment was able to revert the toxicity mediated by CHIKV infection. In addition, FF72 had a direct effect on CHIKV, since the infectivity was completely abolished in the presence of the extract. FF72 treatment also reduced the expression of the major pro-inflammatory mediators overexpressed during CHIKV infection, such as IL-1β, IL-6, IL-8, and MCP-1. Overall, the present study elucidates the potential of FF72 to become a promising candidate of herbal medicine for alphaviruses infections.


Transcription of DNA containing the 5-guanidino-4-nitroimidazole lesion by human RNA polymerase II and bacteriophage T7 RNA polymerase.
Damage in transcribed DNA presents a challenge to the cell because it can partially or completely block the progression of an RNA polymerase, interfering with transcription and compromising gene expression. While blockage of RNA polymerase progression is thought to trigger the recruitment of transcription-coupled DNA repair (TCR), bypass of the lesion can also occur, either error-prone or error-free. Error-prone transcription is often referred to as transcriptional mutagenesis (TM). Elucidating why some lesions pose blocks to transcription elongation while others do not remains a challenging problem. As part of an effort to understand this, we studied transcription past a 5-guanidino-4-nitroimidazole (NI) lesion, using two structurally different RNA polymerases, human RNA polymerase II (hRNAPII) and bacteriophage T7 RNA polymerase (T7RNAP). The NI damage results from the oxidation of guanine in DNA by peroxynitrite, a well known, biologically important oxidant. It is of structural interest because it is a ring-opened and conformationally flexible guanine lesion. Our results show that NI acts as a partial block to T7RNAP while posing a major block to hRNAPII, which has a more constrained active site than T7RNAP. Lesion bypass by T7RNAP induces base misincorporations and deletions opposite the lesion (C>A>-1 deletion >G >>> U), but hRNAPII exhibits error-free transcription although lesion bypass is a rare event. We employed molecular modeling methods to explain the observed blockage or bypass accompanied by nucleotide incorporation opposite the lesion. The results of the modeling studies indicate that NI's multiple hydrogen-bonding capabilities and torsional flexibility are important determinants of its effect on transcription in both enzymes. These influence the kinetics of lesion bypass and may well play a role in TM and TCR in cells.


Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla.
Carbon-13 magnetic resonance spectroscopy (13C MRS) offers a noninvasive method to assess glycogen levels in skeletal muscle and to identify excess glycogen accumulation in patients with glycogen storage disease (GSD). Despite the clinical potential of the method, it is currently not widely used for diagnosis or for follow-up of treatment. While it is possible to perform acceptable 13C MRS at lower fields, the low natural abundance of 13C and the inherently low signal-to-noise ratio of 13C MRS makes it desirable to utilize the advantage of increased signal strength offered by ultra-high fields for more accurate measurements. Concomitant with this advantage, however, ultra-high fields present unique technical challenges that need to be addressed when studying glycogen. In particular, the question of measurement reproducibility needs to be answered so as to give investigators insight into meaningful inter-subject glycogen differences. We measured muscle glycogen levels in vivo in the calf muscle in three patients with McArdle disease (MD), one patient with phosphofructokinase deficiency (PFKD) and four healthy controls by performing 13C MRS at 7T. Absolute quantification of the MRS signal was achieved by using a reference phantom with known concentration of metabolites. Muscle glycogen concentration was increased in GSD patients (31.5±2.9 g/kg w. w.) compared with controls (12.4±2.2 g/kg w. w.). In three GSD patients glycogen was also determined biochemically in muscle homogenates from needle biopsies and showed a similar 2.5-fold increase in muscle glycogen concentration in GSD patients compared with controls. Repeated inter-subject glycogen measurements yield a coefficient of variability of 5.18%, while repeated phantom measurements yield a lower 3.2% system variability. We conclude that noninvasive ultra-high field 13C MRS provides a valuable, highly reproducible tool for quantitative assessment of glycogen levels in health and disease.


Multiplex SYBR Green and duplex TaqMan real-time PCR assays for the detection of Photorhabdus Insect-Related (Pir) toxin genes pirA and pirB.
Acute hepatopancreatic necrosis disease (AHPND), also known as Early mortality syndrome (EMS), is a recently emerged lethal disease that has caused major economic losses in shrimp aquaculture. The etiologic agents are Vibrio spp. that carry Photorhabdus Insect-Related (Pir) toxin genes pirA and pirB. A multiplex SYBR Green real-time PCR was developed that detects pirA, pirB, and two internal control genes, the shrimp 18S rRNA and the bacterial 16S rRNA genes in a single reaction. The pirB primers amplify the 3'-end of the pirB gene allowing the detection of Vibrio spp. mutants that contain a complete deletion of pirA and the partial deletion of pirB. The assay also detects mutants that contain the entire pirA gene and the deletion of the pirB gene. Since both toxin genes are needed for disease development, this assays can distinguish between pathogenic strains of Vibrio spp. that cause AHPND in shrimp and mutants that do not cause disease. The amplicons for pirA, pirB, 18S rRNA and 16S rRNA showed easily distinguishable melting temperatures of 78.21 ± 0.18, 75.20 ± 0.20, 82.28 ± 0.34 and 85.41 ± 0.21 °C respectively. Additionally, a duplex real-time PCR assay was carried out by designing TaqMan probes for the pirA and pirB primers. The diagnostic sensitivity and specificity was compared between the SYBR Green and TaqMan assays. Both assays showed similar sensitivity with a limit of detection being 10 copies for pirA and pirB, and neither assays showed any cross reaction with other known bacterial and viral pathogens in shrimp. The high sensitivity of both assays make them suitable for the detection of low copies of the pirA and pirB genes in AHPND causing Vibrio spp. as well as for detecting non-pathogenic mutants.


Treatment progress and expansion in Japan: From interferon to direct-acting antiviral.
Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.


Scientific networks on Twitter: Analyzing scientists' interactions in the climate change debate.
Scientific issues requiring urgent societal actions-such as climate change-have increased the need for communication and interaction between scientists and other societal actors. Social media platforms facilitate such exchanges. This study investigates who scientists interact with on Twitter, and whether their communication differs when engaging with actors beyond the scientific community. We focus on the climate change debate on Twitter and combine network analysis with automated content analysis. The results show that scientists interact most intensively with their peers, but also communication beyond the scientific community is important. The findings suggest that scientists adjust their communication style to their audience: They use more neutral language when communicating with other scientists, and more words expressing negative emotions when communicating with journalists, civil society, and politicians. Likewise, they stress certainty more when communicating with politicians, indicating that scientists use language strategically when communicating beyond the scientific community.


Low-bandwidth telemedicine for pre- and postoperative evaluation in mobile surgical services.
Low-bandwidth telemedicine was used for the pre- and postoperative evaluation of patients treated by a mobile surgery service in remote Ecuador. Realtime and store-and-forward telemedicine was employed, using PCs connected via the ordinary telephone network. Between February 2002 and July 2003, 144 patients were studied preoperatively and 50 postoperatively. It was possible to establish 20 satisfactory preoperative realtime connections, which allowed good-quality, simultaneous audiovisual transmission. Thus, there were 124 preoperative assessments done by store-and-forward telemedicine and 50 postoperative assessments. Diagnoses and management plans made by a surgeon using telemedicine were compared with those made independently by a second surgeon, who saw the patient face to face. Due to poor quality of the transmitted images, 43 patients were excluded from the preoperative study and 13 from the postoperative study. In the 101 preoperative evaluations, there was agreement in 78 cases (77%); in the 37 postoperative evaluations, there was agreement in 36 cases (97%). Telemedicine may reduce the time required on site for preoperative planning, and may provide reliable postoperative surveillance, thus improving the efficiency of mobile surgery services.


Inverse association between sympathetic nervous system activity and bone mass in middle aged overweight individuals.
Sympathetic nervous system activation in obesity is associated with impaired cardiovascular and metabolic function. Animal studies have shown a direct link between sympathetic nervous activation and bone health but little is known about this link in humans. This study examined whether sympathetic activation may impact bone health in overweight adults. This cross sectional study included 96 overweight or obese middle-aged adults (51 males, mean body mass index: 32.8 kg/m2, mean age: 55.3 years). Multivariate linear regression models evaluated associations between whole body and leg bone mineral density (BMD) and bone mineral content (BMC) derived from dual-energy X-ray absorptiometry and muscle sympathetic nervous system activity (MSNA) measured by microneurography. Older age, male sex and higher weight were associated with higher leg and body BMC and BMD. After adjustment for age, sex and weight, MSNA was significantly inversely associated with total BMC (p = 0.012) and with leg BMC (p < 0.01) but was not associated with either total or leg BMD (p = 0.159 and p = 0.063 respectively). When the analysis was sex specific, the relationships between MSNA and total and leg BMC were only significant in males. Our study indicates that in middle aged overweight or obese males, sympathetic activation may have a deleterious effect on bone mineral content.


Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts.
We have shown that incomplete blockade of the human epidermal growth factor (HER) pathway is a mechanism of resistance to treatment with trastuzumab (T) in HER2-overexpressing tumor xenografts. We now investigate whether the addition of lapatinib (L), a dual HER1/2 kinase inhibitor, to T results in more potent inhibition of the pathway and therefore inhibition of tumor growth, and whether reduced dose and intermittent treatment with the combination is equally effective. Nude mice bearing HER2-overexpressing MCF7/HER2-18 or BT-474 xenograft tumors were treated with L and T, alone or in various combinations with other HER inhibitors. L + T for short duration (14 and 42 days), intermittent administration (14 days on/off), and reduced dosing (half dose) was also investigated. Inhibition of tumor growth, downstream signaling, proliferation, and induction of apoptosis were assessed. All statistical tests were two-sided. L + T was the most effective regimen in both MCF7/HER2-18 and BT-474 xenografts with complete regression (CR) of tumor observed in all mice. Intermittent and reduced dose treatment (½ dose) resulted in high rates of CR and low rates of tumor recurrence that were comparable to full dose continuous treatment. L + T resulted in significantly reduced downstream signaling and proliferation, and increased apoptosis. L + T is a potent and effective combination even when given in reduced dose or intermittent schedule potentially resulting in lower toxicity and reduced cost if translated to patients. These findings warrant timely clinical testing.


Therapeutic trials with levamisole and other agents in NZB/W mice.
The effects of levamisole, ribovirin, and cyclophosphamide in preventing the spontaneous autoimmune disease of NZB/W mice have been evaluated. These drugs all had a significant effect, both in delaying mortality, and in postponing the development of antinuclear antibodies and proteinuria. Single-stranded DNA linked to IgG was also used but had no demonstrable effect. The results of therapeutic studies in murine lupus must be interpreted with caution in relation to the human disease, but as both levamisole and ribovirin are now being used in man, our results suggest that further studies with these drugs are warranted.


Reliability and Validity of the Turkish Version of the Gastrointestinal Symptom Rating Scale.
The purpose of this methodological study is to investigate the validity and reliability of the Turkish version of the Gastrointestinal Symptom Rating Scale (GSRS). The scale was adapted to the Turkish language via backward translation. Content validity was examined by referring to experts. Reliability was examined via test-retest reliability and internal consistency, and validity was examined with divergent and convergent validity. The Epworth Sleepiness Scale (ESS) and the Marlowe-Crowne Social Desirability Scale (MCSDS) were used for divergent validity. As for convergent validity, the Constipation Severity Instrument (CSI) and the Patient Assessment of Constipation Quality of Life Scale (PAC-QOLQ) were utilized. The relationship between the GSRS and the health-related quality of life (36-item short-form health survey [SF-36]) was also analyzed. The study population consisted of patients in orthopedic clinic who volunteered to participate. Test-retest reliability was examined with the participation of 30 patients; internal consistency and validity were examined with 150 patients. Test-retest reliability correlation coefficients of the GSRS varied from 0.39 to 0.87 for all items. For internal consistency, the GSRS's item total correlation was found to be 0.17-0.67, and Cronbach α was 0.82 for all items. There was a positive linear significant correlation between the GSRS, CSI, and PAC-QOLQ. There was no significant correlation between the GSRS, MCSDS, and ESS. Higher GSRS scores inversely correlated with general quality of life (SF-36). The Turkish version of the GSRS has been found to be a reliable and valid instrument for assessing patients' gastrointestinal symptoms. Therefore, this instrument can be confidently used with Turkish individuals.


A Systemic Review on Staphylococcal Scalded Skin Syndrome (SSSS): A Rare and Critical Disease of Neonates.
The symptoms of Staphylococcal scalded skin syndrome (SSSS) include blistering of skin on superficial layers due to the exfoliative toxins released from Staphylococcus aureus. After the acute exfoliation of skin surface, erythematous cellulitis occurs. The SSSS may be confined to few blisters localized to the infection site and spread to severe exfoliation affecting complete body. The specific antibodies to exotoxins and increased clearence of exotoxins decrease the frequency of SSSS in adults. Immediate medication with parenteral anti-staphylococcal antibiotics is mandatory. Mostly, SSSS are resistant to penicillin. Penicillinase resistant synthetic penicillins such as Nafcillin or Oxacillin are prescribed as emergency treatment medicine. If Methicillin-resistant Staphylococcus aureus (MRSA) is suspected), antibiotics with MRSA coverage (e.g., Vancomycin or Linezolid) are indicated. Clindamycin is considered as drug of choice to stop the production of exotoxin from bacteria ribosome. The use of Ringer solution to to balance the fluid loss, followed by maintainence therapy with an objective to maintain the fluid loss from exfoliation of skin, application of Cotrimoxazole on topical surface are greatlly considered to treat the SSSS. The drugs that reduce renal function are avoided. Through this article, an attempt has been made to focus the source, etiology, mechanism, outbreaks, mechanism, clinical manisfestation, treatment and other detail of SSSS.


Fall detection devices and their use with older adults: a systematic review.
Falls represent a significant threat to the health and independence of adults aged 65 years and older. As a wide variety and large number of passive monitoring systems are currently and increasingly available to detect when individuals have fallen, there is a need to analyze and synthesize the evidence regarding their ability to accurately detect falls to determine which systems are most effective. The purpose of this literature review is to systematically assess the current state of design and implementation of fall-detection devices. This review also examines to what extent these devices have been tested in the real world as well as the acceptability of these devices to older adults. A systematic literature review was conducted in PubMed, CINAHL, EMBASE, and PsycINFO from their respective inception dates to June 25, 2013. Articles were included if they discussed a project or multiple projects involving a system with the purpose of detecting a fall in adults. It was not a requirement for inclusion in this review that the system targets persons older than 65 years. Articles were excluded if they were not written in English or if they looked at fall risk, fall detection in children, fall prevention, or a personal emergency response device. Studies were initially divided into those using sensitivity, specificity, or accuracy in their evaluation methods and those using other methods to evaluate their devices. Studies were further classified into wearable devices and nonwearable devices. Studies were appraised for inclusion of older adults in sample and if evaluation included real-world settings. This review identified 57 projects that used wearable systems and 35 projects using nonwearable systems, regardless of evaluation technique. Nonwearable systems included cameras, motion sensors, microphones, and floor sensors. Of the projects examining wearable systems, only 7.1% reported monitoring older adults in a real-world setting. There were no studies of nonwearable devices that used older adults as subjects in either a laboratory or a real-world setting. In general, older adults appear to be interested in using such devices although they express concerns over privacy and understanding exactly what the device is doing at specific times. This systematic review was limited to articles written in English and did not include gray literature. Manual paper screening and review processes may have been subject to interpretive bias. There exists a large body of work describing various fall-detection devices. The challenge in this area is to create highly accurate unobtrusive devices. From this review it appears that the technology is becoming more able to accomplish such a task. There is a need now for more real-world tests as well as standardization of the evaluation of these devices.


Interobserver variability in the pathological assessment of radical prostatectomy specimens: findings of the Laparoscopic Prostatectomy Robot Open (LAPPRO) study.
The aim of this study was to strengthen the validity of future findings in the Laparoscopic Prostatectomy Robot Open (LAPPRO) study by investigating the extent of interobserver variability between local pathologists and re-evaluating reference pathologists. LAPPRO is a Swedish prospective study comparing robot-assisted laparoscopic prostatectomy to open retropubic radical prostatectomy. Patients were recruited from 2008 to 2011. A random selection of 289 prostatectomy specimens was re-evaluated, in a blind fashion, by two reference pathologists from a University Hospital in Denmark and compared with original reports from local pathologists. The exact concordance rate of Gleason score (GS) between local and reference pathologists was 56% (Spearman correlation coefficient 0.54). Exact concordance rates (κ value) for pathological tumour stage (pT), extraprostatic extension (EPE), surgical margin status (SMS) and seminal vesicle invasion (SVI) were 87% (0.63), 86% (0.59), 92% (0.76) and 98% (0.82), respectively. In subanalyses for surgical technique, exact concordance rates of GS, pT, EPE, SMS and SVI were 58%, 83%, 84%, 90% and 97%, respectively, for surgical technique 1 (ST1), compared to 55%, 88%, 87%, 93% and 98%, for surgical technique 2 (ST2). In ST1 specimens undergrading of GS by the local pathologists compared to central review was more common than overgrading (26% vs 16%). The inverse relationship was seen in ST2 specimens (14% vs 32%). Re-evaluation of randomly selected prostatectomy specimens in the LAPPRO cohort showed comparable results compared to previous studies of this kind. A systematic variation in the assessment of GS exists, attributable to individual differences in judgement between pathologists. Dichotomising GS (≤ 7 vs ≥ 8) overcomes the systematic variation.


Incorporating pushing in exclusion-process models of cell migration.
The macroscale movement behavior of a wide range of isolated migrating cells has been well characterized experimentally. Recently, attention has turned to understanding the behavior of cells in crowded environments. In such scenarios it is possible for cells to interact, inducing neighboring cells to move in order to make room for their own movements or progeny. Although the behavior of interacting cells has been modeled extensively through volume-exclusion processes, few models, thus far, have explicitly accounted for the ability of cells to actively displace each other in order to create space for themselves. In this work we consider both on- and off-lattice volume-exclusion position-jump processes in which cells are explicitly allowed to induce movements in their near neighbors in order to create space for themselves to move or proliferate into. We refer to this behavior as pushing. From these simple individual-level representations we derive continuum partial differential equations for the average occupancy of the domain. We find that, for limited amounts of pushing, comparison between the averaged individual-level simulations and the population-level model is nearly as good as in the scenario without pushing. Interestingly, we find that, in the on-lattice case, the diffusion coefficient of the population-level model is increased by pushing, whereas, for the particular off-lattice model that we investigate, the diffusion coefficient is reduced. We conclude, therefore, that it is important to consider carefully the appropriate individual-level model to use when representing complex cell-cell interactions such as pushing.


Cognitive-behavioral psychology: implications for disaster and terrorism response.
Given the personal and societal costs associated with acute impairment and enduring post-traumatic stress disorder (PTSD), the mental health response to disasters is an integral component of disaster response planning. The purpose of this paper is to explore the compatibility between cognitive-behavioral psychology and the disaster mental health model, and explicate how cognitive-behavioral perspectives and intervention methods can enhance the effectiveness of disaster mental health services. It is argued that cognitive-behavioral methods, if matched to the contexts of the disaster and the needs of individuals, will improve efforts to prevent the development of PTSD and other trauma-related problems in survivors of disaster or terrorist events. First, the similarities between models of care underlying both disaster mental health services and cognitive-behavioral therapies are described. Second, examples of prior cognitive-behavioral therapy-informed work with persons exposed to disaster and terrorism are provided, potential cognitive-behavioral therapy applications to disaster and terrorism are explored, and implications of cognitive-behavioral therapy for common challenges in disaster mental health is discussed. Finally, steps that can be taken to integrate cognitive-behavioral therapy into disaster mental health are outlined. The aim is to prompt disaster mental health agencies and workers to consider using cognitive-behavioral therapy to improve services and training, and to motivate cognitive-behavioral researchers and practitioners to develop and support disaster mental health response.


[Analysis of a group of Corynebacterium by numerical taxonomic methods].
Strains (29) of Corynebacterium genus were studied with the use of the method of numerical taxonomy. 48 characteristics (including morphological, tinctorial, cultural and biochemical ones) were analyzed. All the strains tested proved to belong to the same taxon. The present method permitted to reveal various biotypes within the group studied.


Investigating the hydrogen-bonding model of urea denaturation.
The direct binding mechanism for urea-based denaturation of proteins was tested with a thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM). Thermodynamic measurements of the polymer's hydrophobic collapse were complemented by Fourier transform infrared (FTIR) spectroscopy, Stokes radius measurements, and methylated urea experiments. It was found that the lower critical solution temperature (LCST) of PNIPAM decreased as urea was added to the solution. Therefore, urea actually facilitated the hydrophobic collapse of the macromolecule. Moreover, these thermodynamic measurements were strongly correlated with amide I band data which indicated that the decrease in the LCST was coupled to the direct hydrogen bonding of urea to the amide moieties of the polymer. In addition, the hydrogen bonding was found to be highly cooperative, which is consistent with a cross-linking (bivalent binding) mechanism. Cross-linking was confirmed by Stokes radius measurements below the polymer's LCST using gel filtration chromatography. Finally, phase transition measurements with methylurea, dimethylurea, and tetramethylurea indicated that these substituted compounds caused the LCST of PNIPAM to rise with increasing methyl group content. No evidence could be found for the direct binding of any of these methylated ureas to the polymer amide moieties by FTIR. These results are inconsistent with a direct hydrogen-bonding mechanism for the urea-induced denaturation of proteins.


Limits of 'patient-centredness': valuing contextually specific communication patterns.
Globally, doctor-patient communication is becoming synonymous with high-quality health care in the 21st century. However, what is meant by 'good communication' and whether there is consensus internationally remain unclear. Here, we characterise understandings of 'good communication' in future doctors from medical schools in three contextually contrasting continents. Given locally specific socio-cultural influences, we hypothesised that there would be a lack of global consensus on what constitutes 'good communication'. A standardised two-phase methodology was applied in turn to each of three medical schools in the UK, Egypt and India (n = 107 subjects), respectively, in which students were asked: 'What is good communication?' Phase I involved exploratory focus groups to define preliminary themes (mean number of participants per site: 17). Phase II involved thematic confirmation and expansion in one-to-one semi-structured interviews (mean number of participants per site: 18; mean hours of dialogue captured per site: 55). Findings were triangulated and analysed using grounded theory. The overarching theme that emerged from medical students was that 'good communication' requires adherence to certain 'rules of communication'. A shared rule that doctors must communicate effectively despite perceived disempowerment emerged across all sites. However, contradictory culturally specific rules about communication were identified in relation to three major domains: family; gender, and emotional expression. Egyptian students perceived emotional aspects of Western doctors' communication strikingly negatively, viewing these doctors as problematically cold and unresponsive. Contradictory perceptions of 'good communication' in future doctors are found cross-continentally and may contribute to prevalent cultural misunderstandings in medicine. The lack of global consensus on what defines good communication challenges prescriptively taught Western 'patient-centredness' and questions assumptions about international transferability. Health care professionals must be educated openly about flexible, context-specific communication patterns so that they can avoid cultural incompetence and tailor behaviours in ways that optimise therapeutic outcomes wherever they work around the globe.


Humoral immune responsiveness in duck hepatitis B virus-infected ducks.
Immunofluorescence assays with fixed tissue sections were used to characterize antibody reactivity in sera obtained from duck hepatitis B virus-infected ducks. Under conditions of experimental infection, antibody to core antigen but not to surface antigen was detectable. A majority of the ducks infected at 8 days after hatching and a minority of those infected at 1 day after hatching showed a transient anti-core antigen humoral response; this response was stronger in the antibody-positive ducks infected on day 8 than in those infected on day 1. Antiviral antibody was not detected in the sera of ducks congenitally infected with duck hepatitis B virus. Several of the infected ducks, but none of the uninfected ducks, exhibited autoantibody reactivity for alpha-islet-cell-associated antigen.