Alternative endogenous protein processing via an autophagy-dependent pathway compensates for Yersinia-mediated inhibition of endosomal major histocompatibility complex class II antigen presentation.
Extracellular Yersinia pseudotuberculosis employs a type III secretion system (T3SS) for translocating virulence factors (Yersinia outer proteins [Yops]) directly into the cytosol of eukaryotic cells. Recently, we used YopE as a carrier molecule for T3SS-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. We demonstrated that translocation of chimeric YopE/LLO into the cytosol of macrophages by Yersinia results in the induction of a codominant antigen-specific CD4 and CD8 T-cell response in orally immunized mice. In this study, we addressed the requirements for processing and major histocompatibility complex (MHC) class II presentation of chimeric YopE proteins translocated into the cytosol of macrophages by the Yersinia T3SS. Our data demonstrate the ability of Yersinia to counteract exogenous MHC class II antigen presentation of secreted hybrid YopE by the action of wild-type YopE and YopH. In the absence of exogenous MHC class II antigen presentation, an alternative pathway was identified for YopE fusion proteins originating in the cytosol. This endogenous antigen-processing pathway was sensitive to inhibitors of phagolysosomal acidification and macroautophagy, but it did not require the function either of the proteasome or of transporters associated with antigen processing. Thus, by an autophagy-dependent mechanism, macrophages are able to compensate for the YopE/YopH-mediated inhibition of the endosomal MHC class II antigen presentation pathway for exogenous antigens. This is the first report demonstrating that autophagy might enable the host to mount an MHC class II-restricted CD4 T-cell response against translocated bacterial virulence factors. We provide critical new insights into the interaction between the mammalian immune system and a human pathogen.


Stoichiometric Mg:LiNbO(3) as an effective material for nonlinear optics.
Photorefractive damage, optical absorption, photoconductivities, and photogalvanic currents of stoichiometric LiNbO(3) single crystals with different Mg doping levels have been investigated. Nominally pure stoichiometric LiNbO(3) shows lower photorefractive damage resistance than congruent crystal; however, stoichiometric crystals doped with MgO of more than 1.8 mol. % exhibit no measurable photorefractive damage at 532 nm to intensities of as much as 8 MW/cm(2) . This remarkable damage resistance can be attributed not only to increased photoconductivity but also to decreased photogalvanic current. Stoichiometric Mg:LiNbO(3) also demonstrates the shortest absorption edge, 302 nm, and a single-domain nature with low scattering losses.


Motion analysis in two dimensions of radial-ulnar deviation of type I versus type II lunates.
The motions of 2 different types of lunate (type I, no medial hamate facet; type II, medial hamate facet) were evaluated and compared during radial-ulnar deviation of the wrist using radiography and magnetic resonance imaging. Ten right wrists (5 type I and 5 type II lunates) were studied using posteroanterior and lateral x-rays. Six of the 10 normal volunteers (3 type I and 3 type II lunates) were studied using magnetic resonance imaging in 6 positions of radial-ulnar deviation. In the radiographic study the ulnar shift ratio of the lunate (USR), the shortest distance between the proximal ulnar tip of the lunate and the distal ulnar edge of the sigmoid notch of the radius (R-L), the closest distance between the distal ulnar tip of the lunate and the proximal pole of the hamate (L-H), the radius of curvature of the proximal head of the capitate (Cr) on posteroanterior view, and the radiolunate angle on lateral view were measured in each wrist in each of the 6 positions. There were statistically significant differences between type I and II lunates with regard to average maximum ulnar deviation of USR and R-L, total change of USR, R-L distance and L-H distance, average L-H distance and Cr distance in all positions, and average radiolunate angle in neutral and 15 degrees ulnar deviation. In the magnetic resonance imaging study the wrists with a type I lunate did not have contact between the lunate and hamate in any position; the wrists with a type II lunate did have contact between the hamate and the lunate, but only in ulnar deviation. The results of this study demonstrate that the kinematics of a type I lunate are different from those of a type II lunate during radial-ulnar deviation of the wrist.


Muscle damage induced by electrical stimulation.
Electrical stimulation (ES) induces muscle damage that is characterised by histological alterations of muscle fibres and connective tissue, increases in circulating creatine kinase (CK) activity, decreases in muscle strength and development of delayed onset muscle soreness (DOMS). Muscle damage is induced not only by eccentric contractions with ES but also by isometric contractions evoked by ES. Muscle damage profile following 40 isometric contractions of the knee extensors is similar between pulsed current (75 Hz, 400 μs) and alternating current (2.5 kHz delivered at 75 Hz, 400 μs) ES for similar force output. When comparing maximal voluntary and ES-evoked (75 Hz, 200 μs) 50 isometric contractions of the elbow flexors, ES results in greater decreases in maximal voluntary contraction strength, increases in plasma CK activity and DOMS. It appears that the magnitude of muscle damage induced by ES-evoked isometric contractions is comparable to that induced by maximal voluntary eccentric contractions, although the volume of affected muscles in ES is not as large as that of eccentric exercise-induced muscle damage. It seems likely that the muscle damage in ES is associated with high mechanical stress on the activated muscle fibres due to the specificity of motor unit recruitment (i.e., non-selective, synchronous and spatially fixed manner). The magnitude of muscle damage induced by ES is significantly reduced when the second ES bout is performed 2-4 weeks later. It is possible to attenuate the magnitude of muscle damage by "pre-conditioning" muscles, so that muscle damage should not limit the use of ES in training and rehabilitation.


Utility of clinical parameters to identify HIV infection in infants below ten weeks of age in South Africa: a prospective cohort study.
As HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa.HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings. 417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50(th) centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression. A combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.


Hedgehog signaling and the Gli code in stem cells, cancer, and metastases.
The Hedgehog (Hh)-Gli signaling pathway is an essential pathway involved in development and cancer. It controls the Gli code-the sum of all activator and repressor functions of the Gli transcription factors. Through the Gli code, and Gli1 in particular, it modulates the fate and behavior of stem and cancer stem cells, as well as tumor growth and survival in many human cancer types. It also affects recurrence and metastasis and is enhanced in advanced tumors, where it promotes an embryonic stem (ES) cell-like gene expression signature. A central component of this signature, Nanog, is critical for glioblastoma and cancer stem cell survival and expansion. Gli1 activity is also enhanced by several oncogenic proteins, including Ras, Myc, and Akt, and by loss of tumor suppressors, such as p53 and PTEN. The oncogenic load boosts Gli1 levels, which supports tumor progression, and promotes a critical threshold of Gli1 activity that allows cells to enter the metastatic transition. In colon cancers, this transition is defined by enhanced Hh-Gli and, surprisingly, by repressed Wnt-Tcf signaling. Together our data support a model in which the Gli code, and Gli1 in particular, acts as a key sensor that responds to both Hh signals and the oncogenic load. We hypothesize that, in turn, the Gli-regulated ES-like factors induce a reprogramming event in cancer stem cells that promotes high invasion, growth and/or metastasis. Targeting the Gli code, the autoregulatory Gli1-Nanog module and interacting partners and pathways thus offers new therapeutic possibilities.


Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats.
Sea cucumber is widely consumed as a putative functional food. It contains many biologically-active substances, but only limited research on its properties in vivo has been done. The effects of different meals containing Isostichopus badionotus, a sea cucumber from southeast Mexico, on growth performance and body lipid profile in young rats were analyzed. Sea cucumber body wall was either lyophilized, cooked (100 °C, 1 h in water) and lyophilized, or oven-dried (70 °C for 12 h). It was then ground and incorporated into cholesterol-containing diets. I. badionotus meals supported growth and improved lipid profile in rats. In particular, serum cholesterol, low density lipoproteins, triglycerides concentration and atherogenic index values were greatly reduced by some I. badionotus containing diets. Liver total lipids, triglycerides and cholesterol were also reduced. Cooking or heat-treatment of the meals lowered but did not abolish their hypolipidemic potency. Gene expression analysis of several key genes involved in cholesterol and lipid metabolism in liver showed that diets containing I. badionotus repressed the induction of key genes associated with dyslipidemia exerted by cholesterol supplementation. Consumption of I. badionotus from the Yucatan Peninsula is beneficial for dyslipidemia, although biological effect is clearly dependent on preparation method.


Examining DSM criteria for trichotillomania in a dimensional framework: implications for DSM-5 and diagnostic practice.
Diagnosis of trichotillomania (TTM) requires meeting several criteria that aim to embody the core pathology of the disorder. These criteria are traditionally interpreted monothetically, in that they are all equally necessary for diagnosis. Alternatively, a dimensional conceptualization of psychopathology allows for examination of the relatedness of each criterion to the TTM latent continuum. First, to examine the ability of recently removed criteria (B and C) to identify the latent dimensions of TTM psychopathology, such that they discriminate between individuals with low and high degrees of hair pulling severity. Second, to determine the impact of removing criteria B and C on the information content of remaining diagnostic criteria. Third, to determine the psychometric properties of remaining TTM diagnostic criteria that remain largely unchanged in DSM-5; that is, whether they measure distinct or overlapping levels of TTM psychopathology. Fourth, to determine whether information content derived from diagnostic criteria aid in the prediction of disease trajectory (i.e., can relapse propensity be predicted from criteria endorsement patterns). Statistics derived from item response theory were used to examine diagnostic criteria endorsement in 91 adults with TTM who underwent psychotherapy. The removal of two criteria in DSM-5 and psychometric validity of remaining criteria was supported. Additionally, individual trait parameters were used to predict treatment progress, uncovering predictive power where none previously existed. Diagnostic criteria for TTM should be examined in dimensional models, which allow for nuanced and sensitive measurement of core symptomology in treatment contexts.


Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose.
Background and Purpose: Epidemiological data suggests an excess risk of cardiovascular disease (CVD) at low doses (0.05 and 0.1 Gy) of ionizing radiation (IR). Furthermore, the underlying biological and molecular mechanisms of radiation-induced CVD are still unclear. Because damage to the endothelium could be critical in IR-related CVD, this study aimed to identify the effects of radiation on immortalized endothelial cells in the context of atherosclerosis. Material and Methods: Microarrays and RT-qPCR were used to compare the response of endothelial cells irradiated with a single X-ray dose (0.05, 0.1, 0.5, 2 Gy) measured after various post-irradiation (repair) times (1 day, 7 days, 14 days). To consolidate and mechanistically support the endothelial cell response to X-ray exposure identified via microarray analysis, DNA repair signaling (γH2AX/TP53BP1-foci quantification), cell cycle progression (BrdU/7AAD flow cytometric analysis), cellular senescence (β-galactosidase assay with CPRG and IGFBP7 quantification) and pro-inflammatory status (IL6 and CCL2) was assessed. Results: Microarray results indicated persistent changes in cell cycle progression and inflammation. Cells underwent G1 arrest in a dose-dependent manner after high doses (0.5 and 2 Gy), which was compensated by increased proliferation after 1 week and almost normalized after 2 weeks. However, at this point irradiated cells showed an increased β-Gal activity and IGFBP7 secretion, indicative of premature senescence. The production of pro-inflammatory cytokines IL6 and CCL2 was increased at early time points. Conclusions: IR induces pro-atherosclerotic processes in endothelial cells in a dose-dependent manner. These findings give an incentive for further research on the shape of the dose-response curve, as we show that even low doses of IR can induce premature endothelial senescence at later time points. Furthermore, our findings on the time- and dose-dependent response regarding differentially expressed genes, cell cycle progression, inflammation and senescence bring novel insights into the underlying molecular mechanisms of the endothelial response to X-ray radiation. This may in turn lead to the development of risk-reducing strategies to prevent IR-induced CVD, such as the use of cell cycle modulators and anti-inflammatory drugs as radioprotectors and/or radiation mitigators.


Mapping Cortical and Subcortical Asymmetry in Obsessive-Compulsive Disorder: Findings From the ENIGMA Consortium.
Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.


Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer.
Erlotinib is a highly specific epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. This phase II study of erlotinib in patients with HER1/EGFR-expressing non-small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response, survival, and symptom improvement. Fifty-seven patients received an oral, continuous daily dose of 150 mg of erlotinib. Assessments of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, supplemented with a lung cancer module, Quality of Life Questionnaire LC13, was used to measure health-related quality of life. Additional analyses were performed to identify predictors of response and survival. The objective response rate was 12.3% (95% CI, 5.1% to 23.7%). Responses were observed regardless of type or number of prior chemotherapy regimens. Median survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%). Erlotinib therapy was associated with tumor-related symptom improvement. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. One patient experienced toxicity consisting of severe grade 3 rash and diarrhea. Time since diagnosis and good performance status were significant predictors of survival in a multivariate Cox proportional hazards model, whereas HER1/EGFR staining intensity was not. Additionally, survival correlated with the occurrence and severity of rash. Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.


Neovascular Age-Related Macular Degeneration and its Association with Alzheimer's Disease.
In developed countries, people of advanced age go permanently blind most often due to age-related macular degeneration, while at the global level, this disease is the third major cause of blindness, after cataract and glaucoma, according to the World Health Organisation. The number of individuals believed to suffer from the disease throughout the world has been approximated at 50 million. Age-related macular degeneration is classified as non-neovascular (dry, non-exudative) and neovascular (wet, exudative). The exudative form is less common than the non-exudative as it accounts for approximately 10 percent of the cases of the disease. However, it can be much more aggressive and could result in a rapid and severe loss of central vision. Similarly, with age-related macular degeneration, Alzheimer's disease is a late-onset, neurodegenerative disease affecting millions of people worldwide. Both of them are associated with age and share several features, including the presence of abnormal extracellular deposits associated with neuronal degeneration, drusen, and plaques, respectively. The present review article highlights the pathogenesis, clinical features, and imaging modalities used for the diagnosis of neovascular age-related macular degeneration. A thorough overview of the effectiveness of anti-VEGF agents as well as of other treatment modalities that have either lost favour or, are rarely used, is provided in detail. Additionally, the common histologic, immunologic, and pathogenetic features of Alzheimer's disease and age-related macular degeneration are discussed in depth.


Ensemble machine learning on gene expression data for cancer classification.
Whole genome RNA expression studies permit systematic approaches to understanding the correlation between gene expression profiles to disease states or different developmental stages of a cell. Microarray analysis provides quantitative information about the complete transcription profile of cells that facilitate drug and therapeutics development, disease diagnosis, and understanding in the basic cell biology. One of the challenges in microarray analysis, especially in cancerous gene expression profiles, is to identify genes or groups of genes that are highly expressed in tumour cells but not in normal cells and vice versa. Previously, we have shown that ensemble machine learning consistently performs well in classifying biological data. In this paper, we focus on three different supervised machine learning techniques in cancer classification, namely C4.5 decision tree, and bagged and boosted decision trees. We have performed classification tasks on seven publicly available cancerous microarray data and compared the classification/prediction performance of these methods. We have observed that ensemble learning (bagged and boosted decision trees) often performs better than single decision trees in this classification task.


"Micro-pottery"--marangoni effect driven assembly of amphiphilic fibers.
We report spontaneous supra-assembly of fibrous surfactant crystallites at the air-solution interface resulting in spectacular arrays of two-dimensional spiral and three-dimensional "micro-pottery"-like superstructures. Surface pressure differential driven bending of the embryonic fiber nuclei and Marangoni convection driven fiber migration/alignment appear to be the causal factors behind this phenomenon. The assemblies form at specific crystal-growth velocities dictated by the relative time scales for fiber bending/alignment and their rigidification/immobilization as they grow. Although our studies are restricted to a specific class of amphiphiles, namely, alkaline metal salts of linear fatty acids, the phenomenon should be generic to amphiphilic molecules that crystallize into flexible fibers.


Proteomic LC-MS analysis of Arabidopsis cytosolic ribosomes: Identification of ribosomal protein paralogs and re-annotation of the ribosomal protein genes.
Arabidopsis thaliana cytosolic ribosomes are large complexes containing eighty-one distinct ribosomal proteins (r-proteins), four ribosomal RNAs (rRNA) and a plethora of associated (non-ribosomal) proteins. In plants, r-proteins of cytosolic ribosomes are each encoded by two to seven different expressed and similar genes, forming an r-protein family. Distinctions in the r-protein coding sequences of gene family members are a source of variation between ribosomes. We performed proteomic investigation of actively translating cytosolic ribosomes purified using both immunopurification and a classic sucrose cushion centrifugation-based protocol from plants of different developmental stages. Both 1D and 2D LC-MS(E) with data-independent acquisition as well as conventional data-dependent MS/MS procedures were applied. This approach provided detailed identification of 165 r-protein paralogs with high coverage based on proteotypic peptides. The detected r-proteins were the products of the majority (68%) of the 242 cytosolic r-protein genes encoded by the genome. A total of 70 distinct r-proteins were identified. Based on these results and information from DNA microarray and ribosome footprint profiling studies a re-annotation of Arabidopsis r-proteins and genes is proposed. This compendium of the cytosolic r-protein proteome will serve as a template for future investigations on the dynamic structure and function of plant ribosomes. Translation is one of the most energy demanding processes in a living cell and is therefore carefully regulated. Translational activity is tightly linked to growth control and growth regulating mechanism. Recently established translational profiling technologies, including the profiling of mRNAs associated with polysomes and the mapping of ribosome footprints on mRNAs, have revealed that the expression of gene expression is often fine-tuned by differential translation of gene transcripts. The eukaryotic ribosome, the hub of these important processes, consists of close to eighty different proteins (depending on species) and four large RNAs assembled into two highly conserved subunits. In plants and to lesser extent in yeast, the r-proteins are encoded by more than one actively transcribed gene. As r-protein gene paralogs frequently do not encode identical proteins and are regulated by growth conditions and development, in vivo ribosomes are heterogeneous in their protein content. The regulatory and physiological importance of this heterogeneity is unknown. Here, an improved annotation of the more than two hundred r-protein genes of Arabidopsis is presented that combines proteomic and advanced mRNA expression data. This proteomic investigation and re-annotation of Arabidopsis ribosomes establish a base for future investigations of translational control in plants.


Ascent of sap in trees.
Experimental results concerning the ascent of sap in the xylem are usually interpreted in terms of gradients of hydrostatic pressure in the xylem conduits. In this report an alternative model is proposed that is equally consistent with the experimental results: under static conditions the water column is supported by a gradient in the chemical activity of the water, and the hydrostatic pressure is constant throughout. Observations that support the new model are cited, and experiments are suggested that would permit a choice between the two models.


Is Referral to Home Health Rehabilitation After Inpatient Rehabilitation Facility Associated With 90-Day Hospital Readmission for Adult Patients With Stroke?
We examined the association between home health rehabilitation referral and 90-day risk-adjusted hospital readmission after discharge from inpatient rehabilitation facilities among adult patients recovering from stroke (N = 1219). A secondary data analysis of the 2005-2006 Stroke Recovery in Underserved Population database. A logistic regression model, multilevel model, and the propensity score inverse probability weighting model were used to evaluate the risk of 90-day rehospitalization between patients with stroke who received a referral for home health rehabilitation and those who did not receive a home health rehabilitation referral at inpatient rehabilitation facility discharge. The regression, multilevel, and propensity score inverse probability weighting models indicated that inpatient rehabilitation facility patients with stroke who received home health rehabilitation referral had substantially lower odds of 90-day rehospitalization after inpatient rehabilitation facility discharge compared with those who were not referred to home health (odds ratio = 0.325, 95% confidence interval = 0.138-0.764; odds ratio = 0.340, 95% confidence interval = 0.139-0.832; odds ratio = 0.407, 95% confidence interval = 0.183-0.906, respectively). Our findings suggest the importance of continuation of care (home health) after hospitalization and intense inpatient rehabilitation for stroke. Additional research is needed to establish appropriate use criteria and explore potential underuse of home health services as well as the benefits for follow-up outpatient services for those who do not qualify for home health at inpatient rehabilitation facility discharge.


Familial rates of affective disorder. A report from the National Institute of Mental Health Collaborative Study.
We examined familial rates of affective disorder and related illness in a cohort of 955 probands studied at five centers in the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression: Boston, Chicago, Iowa City, New York, and St. Louis. Six hundred sixteen of these probands were entered into a family study, and 3423 of their first-degree relatives were evaluated. The probands were divided into five diagnostic groups: schizoaffective-bipolar (n = 37), schizoaffective-depressed (n = 18), bipolar I (n = 151), bipolar II (n = 76), and unipolar (n = 330). The relatives of bipolar I probands had a higher rate of bipolar I illness than the relatives of unipolar probands, but the relatives of unipolar probands did not have a higher rate of unipolar illness than the relatives of bipolar I probands. The relatives of probands with schizoaffective disorder, depressed subtype, had a higher rate of schizophrenia than the relatives of schizoaffective-bipolar probands, suggesting that bipolar schizoaffective disorder may be closer to pure affective disorder while schizoaffective depression may be closer to schizophrenia. An increase in bipolar II illness was also observed in the relatives of bipolar II probands. Overall, these data support the widely accepted distinction between bipolar and unipolar affective disorders.


Chromosomal Differentiation in Genetically Isolated Populations of the Marsh-Specialist Crocidura suaveolens (Mammalia: Soricidae).
The genus Crocidura represents a remarkable model for the study of chromosome evolution. This is the case of the lesser white-toothed shrew (Crocidura suaveolens), a representative of the Palearctic group. Although continuously distributed from Siberia to Central Europe, C. suaveolens is a rare, habitat-specialist species in the southwesternmost limit of its distributional range, in the Gulf of Cádiz (Iberian Peninsula). In this area, C. suaveolens is restricted to genetically isolated populations associated to the tidal marches of five rivers (Guadiana, Piedras, Odiel, Tinto and Guadalquivir). This particular distributional range provides a unique opportunity to investigate whether genetic differentiation and habitat specialization was accompanied by chromosomal variation. In this context, the main objective of this study was to determinate the chromosomal characteristics of the habitat-specialist C. suaveolens in Southwestern Iberia, as a way to understand the evolutionary history of this species in the Iberian Peninsula. A total of 41 individuals from six different populations across the Gulf of Cádiz were collected and cytogenetically characterized. We detected four different karyotypes, with diploid numbers (2n) ranging from 2n = 40 to 2n = 43. Two of them (2n = 41 and 2n = 43) were characterized by the presence of B-chromosomes. The analysis of karyotype distribution across lineages and populations revealed an association between mtDNA population divergence and chromosomal differentiation. C. suaveolens populations in the Gulf of Cádiz provide a rare example of true karyotypic polymorphism potentially associated to genetic isolation and habitat specialization in which to investigate the evolutionary significance of chromosomal variation in mammals and their contribution to phenotypic and ecological divergence.


Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75.
In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.


Prognostic significance of annexin VII expression in glioblastomas multiforme in humans.
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. It is nearly uniformly fatal, with a median survival time of approximately 1 year, despite modem treatment modalities. Nevertheless, a range of survival times exists around this median. Efforts to understand why some patients live longer or shorter than the average may provide insight into the biology of these neoplasms. The annexin VII (ANX7) gene is located on the human chromosome 10q21, a site long hypothesized to harbor tumor suppressor genes associated with prostate and other cancers. To test whether ANX7 expression might be a predictor for GBMs, we examined ANX7 expression, p53 accumulation, and the MIB-1 labeling index in a retrospective series of 99 GBMs. In all 99 cases, the patient's age, Karnofsky Performance Scale (KPS) score before surgery, extent of surgery, tumor location, and immunohistochemical features were analyzed using univariate and multivariate analyses to identify whether any significance exists among ANX7 expression, p53 accumulation, the MIB-1 labeling index, and survival time. Kaplan-Meier analyses demonstrated that a higher KPS score before surgery (< 0.0001), total tumor excision (p = 0.0072), young patient age (p = 0.03), and ANX7 expression (p = 0.0006) correlated with longer survival. Multivariate Cox regression analyses demonstrated that ANX7 expression was the strongest predictor of outcome (p < 0.0001), independent of all other variables. In addition, ANX7 expression correlated with higher MIB-1 immunostaining, but did not correlate with p53 accumulation. Moreover, a significant positive correlation was observed between p53 and MIB-1 staining. These findings indicate that a higher KPS score before surgery, total tumor excision, young patient age, and ANX7 expression correlate with longer survival in patients with GBMs. Multivariate Cox regression analyses demonstrated that ANX7 expression was the strongest predictor of outcome (p < 0.0001) and was independent of all other variables.


FlgD is a scaffolding protein needed for flagellar hook assembly in Salmonella typhimurium.
FlgD is known to be absolutely required for hook assembly, yet it has not been detected in the mature flagellum. We have overproduced and purified FlgD and raised an antibody against it. By using this antibody, we have detected FlgD in substantial amounts in isolated basal bodies from flgA, flgE, flgH, flgI, flgK, and fliK mutants, in much smaller amounts in those from the wild type and flgL, fliA, fliC, fliD, and fliE mutants, and not at all in those from flgB, flgD, flgG, and flgJ mutants. In terms of the morphological assembly pathway, these results indicate that FlgD is first added to the structure when the rod is completed and is discarded when the hook, having reached its mature length, has the first of the hook-filament junction proteins, FlgK, added to its tip. Immunoelectron microscopy established that FlgD initially is located at the distal end of the rod and eventually is located at the distal end of the hook. Thus, it appears to act as a hook-capping protein to enable assembly of hook protein subunits, much as another flagellar protein, FliD, does for the flagellin subunits of the filament. However, whereas FliD is associated with the filament tip indefinitely, FlgD is only transiently associated with the hook tip; i.e., it acts as a scaffolding protein. When FlgD was added to the culture medium of a flgD mutant, cells gained motility; thus, although the hook cap is normally added endogenously, it can be added exogenously. When culture media were analyzed for the presence of hook protein, it was found only with the flgD mutant and, in smaller amounts, the fliK (polyhook) mutant. Thus, although FlgD is needed for assembly of hook protein, it is not needed for its export.


Depression of cardiac sarcolemmal phospholipase D activity by oxidant-induced thiol modification.
Myocardial phospholipase D (PLD) is primarily localized at the sarcolemmal level and selectively hydrolyzes phosphatidylcholine to form phosphatidic acid as part of the signal transduction mechanisms for regulating Ca2+ movements in the heart. Since the myocardial cell damage induced by oxidative stress is associated with abnormalities in Ca2+ homeostasis and thiol status, we examined the thiol group dependence and the effects of oxidant species on this enzyme. Sarcolemmal membranes isolated from rat heart were exposed to several types of thiol group modifiers. Alkylation with N-ethylmaleimide or methyl methanethiosulfonate, mercaptide formation with p-chloromercuriphenylsulfonic acid, and thiol-disulfide exchange with 5,5'-dithio-bis(2-nitrobenzoate) depressed sarcolemmal PLD activity; in all cases the depression was prevented by dithiothreitol. At different concentrations of N-ethylmaleimide the PLD depression correlated well (r = 0.98) with the decrease in total thiol group content of the membrane. The enzyme activity was not affected by xanthine-xanthine oxidase, a superoxide anion-generating system, but was depressed by hydrogen peroxide (H2O2) in a concentration-dependent manner. This inhibitory effect was prevented by catalase as well as by dithiothreitol, but not by D-mannitol. The effect of a hydroxyl radical-generating system (Fenton reaction) could not be assessed because of an interfering direct inhibition by Fe2+. Dithiothreitol was also able to restore PLD activity in H2O2-pretreated membranes and to prevent a severe deactivation of the enzyme by hypochlorous acid (HOCI). Protection by glutathione and inhibition by its oxidized form were also observed.(ABSTRACT TRUNCATED AT 250 WORDS)


Reassessing hepatocellular carcinoma staging in a changing patient population.
Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at oncology centers, which has altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis. A total of 438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier analysis was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell's Correspondence Index compared the staging systems' ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed. Median patient OS was 13.9 months; 165 patients (37.7%) had no cirrhosis and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis. Our results advocate the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patient risk-stratification and, ultimately, treatment decisions.


LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta.
Polymorphisms in the beta chain of the high affinity receptor for IgE (Fc epsilon RI-beta, MS4A2) are consistently associated with traits underlying asthma and atopy (immunoglobulin E-mediated allergy). However, the causal variants and haplotypes underlying disease have not yet been identified. Maternal effects, with association confined to maternally derived alleles, have been shown in some studies but not in others. We have therefore extended the known sequence and systematically detected polymorphisms across an 18.1 Kb genomic region that includes Fc epsilon RI-beta. Association testing in two panels of subjects showed the presence of single-nucleotide polymorphisms (SNPs) affecting prick skin tests and specific IgE responses in several clusters. Stepwise analyses indicated that the clusters represent independent effects. Interferon regulatory factor 2 (IRF-2) sites were altered by significantly associated SNPs in two regions. Strong association to maternally derived alleles was seen in one panel of subjects and not in the other. Maternal and non-maternally derived associations tended to share the same SNP clusters, but associations were stronger in the presence of maternal effects. Two regions of increased CpG concentration were identified in Fc epsilon RI-beta. One of these approximated a SNP cluster that showed strong association and maternal effects, providing a potential substrate for epigenetic effects.


Selective growth inhibition of human breast cancer cells by graviola fruit extract in vitro and in vivo involving downregulation of EGFR expression.
The epidermal growth factor receptor (EGFR) is an oncogene frequently overexpressed in breast cancer (BC), and its overexpression has been associated with poor prognosis and drug resistance. EGFR is therefore a rational target for BC therapy development. This study demonstrated that a graviola fruit extract (GFE) significantly downregulated EGFR gene expression and inhibited the growth of BC cells and xenografts. GFE selectively inhibited the growth of EGFR-overexpressing human BC (MDA-MB-468) cells (IC(50) = 4.8 μg/ml) but had no effect on nontumorigenic human breast epithelial cells (MCF-10A). GFE significantly downregulated EGFR mRNA expression, arrested cell cycle in the G0/G1 phase, and induced apoptosis in MDA-MB-468 cells. In the mouse xenograft model, a 5-wk dietary treatment of GFE (200 mg/kg diet) significantly reduced the protein expression of EGFR, p-EGFR, and p-ERK in MDA-MB-468 tumors by 56%, 54%, and 32.5%, respectively. Overall, dietary GFE inhibited tumor growth, as measured by wet weight, by 32% (P < 0.01). These data showed that dietary GFE induced significant growth inhibition of MDA-MB-468 cells in vitro and in vivo through a mechanism involving the EGFR/ERK signaling pathway, suggesting that GFE may have a protective effect for women against EGFR-overexpressing BC.


Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination.
To provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV) and cervical cancer, explicitly incorporating uncertainty about the natural history of disease. We developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distributions, and simulations undertaken with each set. Through systematic reviews and formal data synthesis, we established multiple epidemiologic targets for model calibration, including age-specific prevalence of HPV by type, age-specific prevalence of cervical intraepithelial neoplasia (CIN), HPV type distribution within CIN and cancer, and age-specific cancer incidence. For each set of sampled input parameters, likelihood-based goodness-of-fit (GOF) scores were computed based on comparisons between model-predicted outcomes and calibration targets. Using 50 randomly resampled, good-fitting parameter sets, we assessed the external consistency and face validity of the model, comparing predicted screening outcomes to independent data. To illustrate the advantage of this approach in reflecting parameter uncertainty, we used the 50 sets to project the distribution of health outcomes in U.S. women under different cervical cancer prevention strategies. Approximately 200 good-fitting parameter sets were identified from 1,000,000 simulated sets. Modeled screening outcomes were externally consistent with results from multiple independent data sources. Based on 50 good-fitting parameter sets, the expected reductions in lifetime risk of cancer with annual or biennial screening were 76% (range across 50 sets: 69-82%) and 69% (60-77%), respectively. The reduction from vaccination alone was 75%, although it ranged from 60% to 88%, reflecting considerable parameter uncertainty about the natural history of type-specific HPV infection. The uncertainty surrounding the model-predicted reduction in cervical cancer incidence narrowed substantially when vaccination was combined with every-5-year screening, with a mean reduction of 89% and range of 83% to 95%. We demonstrate an approach to parameterization, calibration and performance evaluation for a U.S. cervical cancer microsimulation model intended to provide qualitative and quantitative inputs into decisions that must be taken before long-term data on vaccination outcomes become available. This approach allows for a rigorous and comprehensive description of policy-relevant uncertainty about health outcomes under alternative cancer prevention strategies. The model provides a tool that can accommodate new information, and can be modified as needed, to iteratively assess the expected benefits, costs, and cost-effectiveness of different policies in the U.S.


Ectomycorrhizal fungi drive positive phylogenetic plant-soil feedbacks in a regionally dominant tropical plant family.
While work in temperate forests suggests that there are consistent differences in plant-soil feedback (PSF) between plants with arbuscular and ectomycorrhizal associations, it is unclear whether these differences exist in tropical rainforests. We tested the effects of mycorrhizal type, phylogenetic relationships to overstory species, and soil fertility on the growth of tree seedlings in a tropical Bornean rainforest with a high diversity of both ectomycorrhizal and arbuscular mycorrhizal trees. We found that ectomycorrhizal tree seedlings had higher growth in soils conditioned by close relatives and that this was associated with higher mycorrhizal colonization. By contrast, arbuscular mycorrhizal tree seedlings generally grew more poorly in soils conditioned by close relatives. For ectomycorrhizal species, the phylogenetic trend was insensitive to soil fertility. For arbuscular mycorrhizal seedlings, however, the effect of growing in soils conditioned by close relatives became increasingly negative as soil fertility increased. Our results demonstrate consistent effects of mycorrhizal type on plant-soil feedbacks across forest biomes. The positive effects of ectomycorrhizal symbiosis may help explain biogeographic variation across tropical forests, such as familial dominance of the Dipterocarpaceae in southeast Asia. However, positive feedbacks also raise questions about the role of PSFs in maintaining tropical diversity.


Quantification of absolute myocardial perfusion in patients with coronary artery disease: comparison between cardiovascular magnetic resonance and positron emission tomography.
The aim of this study was to compare fully quantitative cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) myocardial perfusion and myocardial perfusion reserve (MPR) measurements in patients with coronary artery disease (CAD). Absolute quantification of myocardial perfusion and MPR with PET have proven diagnostic and prognostic roles in patients with CAD. Quantitative CMR perfusion imaging has been established more recently and has been validated against PET in normal hearts. However, there are no studies comparing fully quantitative CMR against PET perfusion imaging in patients with CAD. Forty-one patients with known or suspected CAD prospectively underwent quantitative (13)N-ammonia PET and CMR perfusion imaging before coronary angiography. The CMR-derived MPR (MPR(CMR)) correlated well with PET-derived measurements (MPR(PET)) (r = 0.75, p < 0.0001). MPR(CMR) and MPR(PET) for the 2 lowest scoring segments in each coronary territory also correlated strongly (r = 0.79, p < 0.0001). Absolute CMR perfusion values correlated significantly, but weakly, with PET values both at rest (r = 0.32; p = 0.002) and during stress (r = 0.37; p < 0.0001). Area under the receiver-operating characteristic curve for MPR(PET) to detect significant CAD was 0.83 (95% confidence interval: 0.73 to 0.94) and for MPR(CMR) was 0.83 (95% confidence interval: 0.74 to 0.92). An MPR(PET) ≤1.44 predicted significant CAD with 82% sensitivity and 87% specificity, and MPR(CMR) ≤1.45 predicted significant CAD with 82% sensitivity and 81% specificity. There is good correlation between MPR(CMR) and MPR(PET.) For the detection of significant CAD, MPR(PET) and MPR(CMR) seem comparable and very accurate. However, absolute perfusion values from PET and CMR are only weakly correlated; therefore, although quantitative CMR is clinically useful, further refinements are still required.


Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop.
Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries. However, during the past decades, the United States has fared worse in many key health domains resulting in shorter life expectancy and poorer health-a health disadvantage. The National Heart, Lung, and Blood Institute convened a panel of national and international health experts and stakeholders for a Think Tank meeting to explore the U.S. health disadvantage and to seek specific recommendations for implementation research opportunities for heart, lung, blood, and sleep disorders. Recommendations for National Heart, Lung, and Blood Institute consideration were made in several areas including understanding the drivers of the disadvantage, identifying potential solutions, creating strategic partnerships with common goals, and finally enhancing and fostering a research workforce for implementation research. Key recommendations included exploring why the United States is doing better for health indicators in a few areas compared with peer countries; targeting populations across the entire socioeconomic spectrum with interventions at all levels in order to prevent missing a substantial proportion of the disadvantage; assuring partnership have high-level goals that can create systemic change through collective impact; and finally, increasing opportunities for implementation research training to meet the current needs. Connecting with the research community at large and building on ongoing research efforts will be an important strategy. Broad partnerships and collaboration across the social, political, economic, and private sectors and all civil society will be critical-not only for implementation research but also for implementing the findings to have the desired population impact. Developing the relevant knowledge to tackle the U.S. health disadvantage is the necessary first step to improve U.S. health outcomes.


Back from the brink: a mesenchymal stem cell infusion rescues kidney function in acute experimental rhabdomyolysis.
Systemic administration of mesenchymal stem (stromal) cells (MSCs) has shown benefit in a range of experimental models of acute kidney injury, although the reported mechanisms of action and requirement for MSC localization to the kidney have varied. Geng and colleagues now demonstrate that a single intravenous infusion of MSCs given 6 hours after induction of acute muscle necrosis (rhabdomyolysis) robustly ameliorates the resulting acute kidney injury and promotes early intra-renal accumulation of CD206+ (M2) macrophages. The benefit occurred in the absence of MSC localization to the kidney and could be reproduced by adoptive transfer of ex vivo-programmed M2 macrophages.


Pulmonary Hypertension Is Associated With a Higher Risk of Heart Failure Hospitalization and Mortality in Patients With Chronic Kidney Disease: The Jackson Heart Study.
African Americans develop chronic kidney disease and pulmonary hypertension (PH) at disproportionately high rates. Little is known whether PH heightens the risk of heart failure (HF) admission or mortality among chronic kidney disease patients, including patients with non-end-stage renal disease. We analyzed African Americans participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2 or urine albumin/creatinine >30 mg/g) and available echocardiogram-derived pulmonary artery systolic pressure (PASP) from the Jackson Heart Study (N=408). We used Cox models to assess whether PH (PASP>35 mm Hg) was associated with higher rates of HF hospitalization and mortality. In a secondary, cross-sectional analysis, we examined the relationship between cystatin C (a marker of renal function) and PASP and potential mediators, including BNP (B-type natriuretic peptide) and endothelin-1. In our cohort, the mean age was 63±13 years, 70% were female, 78% had hypertension, and 22% had PH. Eighty-five percent of the participants had an estimated glomerular filtration rate >30 mL/min per 1.73 m2. During follow-up, 13% were hospitalized for HF and 27% died. After adjusting for potential confounders, including BNP, PH was found to be associated with HF hospitalization (hazard ratio, 2.37; 95% confidence interval, 1.15-4.86) and the combined outcome of HF hospitalization or mortality (hazard ratio, 1.84; confidence interval, 1.09-3.10). Log cystatin C was directly associated with PASP (adjusted β =2.5 [95% confidence interval, 0.8-4.1] per standard deviation change in cystatin C). Mediation analysis showed that BNP and endothelin-1 explained 56% and 40%, respectively, of the indirect effects between cystatin C and PASP. Among African Americans with chronic kidney disease, PH, which is likely pulmonary venous hypertension, was associated with a higher risk of HF admission and mortality.


Emotional face processing across neurodevelopmental disorders: a dynamic faces study in children with autism spectrum disorder, attention deficit hyperactivity disorder and obsessive-compulsive disorder.
Autism spectrum disorder (ASD) is classically associated with poor face processing skills, yet evidence suggests that those with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) also have difficulties understanding emotions. We determined the neural underpinnings of dynamic emotional face processing across these three clinical paediatric groups, including developmental trajectories, compared with typically developing (TD) controls. We studied 279 children, 5-19 years of age but 57 were excluded due to excessive motion in fMRI, leaving 222: 87 ASD, 44 ADHD, 42 OCD and 49 TD. Groups were sex- and age-matched. Dynamic faces (happy, angry) and dynamic flowers were presented in 18 pseudo-randomized blocks while fMRI data were collected with a 3T MRI. Group-by-age interactions and group difference contrasts were analysed for the faces vs. flowers and between happy and angry faces. TD children demonstrated different activity patterns across the four contrasts; these patterns were more limited and distinct for the NDDs. Processing happy and angry faces compared to flowers yielded similar activation in occipital regions in the NDDs compared to TDs. Processing happy compared to angry faces showed an age by group interaction in the superior frontal gyrus, increasing with age for ASD and OCD, decreasing for TDs. Children with ASD, ADHD and OCD differentiated less between dynamic faces and dynamic flowers, with most of the effects seen in the occipital and temporal regions, suggesting that emotional difficulties shared in NDDs may be partly attributed to shared atypical visual information processing.


Prevalence and comorbidity in a Swedish adolescent community sample - gambling, gaming, substance use, and other psychiatric disorders.
This study investigates a broad spectrum of psychiatric disorders, substance use disorders, gambling, and internet gaming disorders in Swedish 18-year-old boys and girls with the aim of estimating the prevalence of disorders and comorbidity. We used a two-phase design with screening to detect candidates for clinical interviews. Screening included 949 adolescents (55.6% girls), out of which 758 adolescents (57.0% girls) were selected for interview with at least one of four instruments: M.I.N.I., ADDIS, NODS and IGDS. Of these, 387 (61.2% girls) were interviewed. Gender separated prevalence was estimated on the assumption that those selected but not interviewed had the same distribution as those interviewed based on similar outcomes above screening cut-offs. Comorbidity between types of disorders was estimated on similar assumptions. In addition, comorbidity between dyads of the ten most common specified disorders was calculated based on recorded data without these assumptions. We estimated that 14.6% met the criteria of a substance use disorder (SUD), mostly concerning alcohol and more frequent in girls than in boys. Those meeting the criteria lifetime of at least one of 16 other psychiatric disorders were 26.7%, more than twice as frequent in girls compared to boys, and with depression being the most common disorder. Gambling and gaming disorders were found almost exclusively in boys, of which 5.8% met the criteria for gambling, and 2.3% for gaming disorders. Of girls with a SUD, 40% also had a psychiatric disorder, while on the other hand more than 28% of girls with a psychiatric disorder also had a SUD. In boys with a SUD, 22% had another psychiatric disorder, while 15% of those with a psychiatric disorder also had a SUD. Psychiatric comorbidity is common in SUDs in adolescents, which calls for screening and diagnostic efforts in young patients presenting with symptoms of SUDs. Girls with SUDs are at higher risk of also suffering from psychiatric conditions. Gambling and gaming disorders appear in a substantial minority of adolescents and warrant further study of their comorbidity. Since prevalences and comorbidity were estimated on the assumptions mentioned, some caution in interpreting the results is needed.


Accuracy of Three-Dimensional Planning in Surgery-First Orthognathic Surgery: Planning Versus Outcome.
The benefit of computer-assisted planning in orthognathic surgery (OGS) has been extensively documented over the last decade. This study aimed to evaluate the accuracy of three-dimensional (3D) virtual planning in surgery-first OGS. Fifteen patients with skeletal class III malocclusion who underwent bimaxillary OGS with surgery-first approach were included. A composite skull model was reconstructed using data from cone-beam computed tomography and stereolithography from a scanned dental cast. Surgical procedures were simulated using Simplant O&O software, and the virtual plan was transferred to the operation room using 3D-printed splints. Differences of the 3D measurements between the virtual plan and postoperative results were evaluated, and the accuracy was reported using root mean square deviation (RMSD) and the Bland-Altman method. The virtual planning was successfully transferred to surgery. The overall mean linear difference was 0.88 mm (0.79 mm for the maxilla and 1 mm for the mandible), and the overall mean angular difference was 1.16°. The RMSD ranged from 0.86 to 1.46 mm and 1.27° to 1.45°, within the acceptable clinical criteria. In this study, virtual surgical planning and 3D-printed surgical splints facilitated the diagnosis and treatment planning, and offered an accurate outcome in surgery-first OGS.


A multifunctional Co-based metal-organic framework: heterogeneous catalysis, chemiluminescence sensing and moisture-dependent solvatochromism.
Crystalline materials with multi-catalytic applications are of great value to both fundamental research and practical applications. The platform of metal-organic frameworks (MOFs) is utilized to fabricate a microporous versatile catalyst with high stability. Self-assembly of a flexible ligand, 4-(4-carboxybenzylamino)benzoic acid (H2CBBA), with Co(ii) resulted in a 3D framework, CBBA-Co, with Co3O clusters exposed in the zigzag channels. Upon in situ activation, CBBA-Co exhibited multiple heterogeneous catalytic activities. Theoretical calculations were carried out to give insights into the catalytic process. In addition, CBBA-Co also showed promising potential in optical sensing by virtue of its catalytic activity. The luminol chemiluminescence was greatly enhanced by CBBA-Co, and linear determination of the concentration of H2O2 in the range of 0-30% was established. The successful implementation of CBBA-Co indicates the feasibility and promising future of employing MOFs as an efficient platform for the fabrication and study of multifunctional catalysts, both experimentally and theoretically.


Research quality and transparency, outcome measurement and evidence for safety and effectiveness in robot-assisted surgery: systematic review.
Robot-assisted surgery (RAS) has potential panspecialty surgical benefits. High-quality evidence for widespread implementation is lacking. This systematic review aimed to assess the RAS evidence base for the quality of randomized evidence on safety and effectiveness, specialty 'clustering', and outcomes for RAS research. A systematic review was undertaken according to PRISMA guidelines. All pathologies and procedures utilizing RAS were included. Studies were limited to RCTs, the English language and publication within the last decade. The main outcomes selected for the review design were safety and efficacy, and study purpose. Secondary outcomes were study characteristics, funding and governance. Searches identified 7142 titles, from which 183 RCTs were identified for data extraction. The commonest specialty was urology (35·0 per cent). There were just 76 unique study populations, indicating significant overlap of publications; 103 principal studies were assessed further. Only 64·1 per cent of studies reported a primary outcome measure, with 29·1 per cent matching their registration/protocol. Safety was assessed in 68·9 per cent of trials; operative complications were the commonest measure. Forty-eight per cent of trials reported no significant difference in safety between RAS and comparator, and 11 per cent reported RAS to be superior. Efficacy or effectiveness was assessed in 80·6 per cent of trials; 43 per cent of trials showed no difference between RAS and comparator, and 24 per cent reported that RAS was superior. Funding was declared in 47·6 per cent of trials. The evidence base for RAS is of limited quality and variable transparency in reporting. No patterns of harm to patients were identified. RAS has potential to be beneficial, but requires continued high-quality evaluation.


Natural variation for seed dormancy in Arabidopsis is regulated by additive genetic and molecular pathways.
Timing of germination is presumably under strong natural selection as it determines the environmental conditions in which a plant germinates and initiates its postembryonic life cycle. To investigate how seed dormancy is controlled, quantitative trait loci (QTL) analyses has been performed in six Arabidopsis thaliana recombinant inbred line populations by analyzing them simultaneously using a mixed model QTL approach. The recombinant inbred line populations were derived from crosses between the reference accession Landsberg erecta (Ler) and accessions from different world regions. In total, 11 delay of germination (DOG) QTL have been identified, and nine of them have been confirmed by near isogenic lines (NILs). The absence of strong epistatic interactions between the different DOG loci suggests that they affect dormancy mainly by distinct genetic pathways. This was confirmed by analyzing the transcriptome of freshly harvested dry seeds of five different DOG NILs. All five DOG NILs showed discernible and different expression patterns compared with the expression of their genetic background Ler. The genes identified in the different DOG NILs represent largely different gene ontology profiles. It is proposed that natural variation for seed dormancy in Arabidopsis is mainly controlled by different additive genetic and molecular pathways rather than epistatic interactions, indicating the involvement of several independent pathways.


How do people understand overtesting and overdiagnosis? Systematic review and meta-synthesis of qualitative research.
The public should be informed about overtesting and overdiagnosis. Diverse qualitative studies have examined public understandings of this information. A synthesis was needed to systematise the body of evidence and yield new, generalisable insights. Synthesise data from qualitative studies exploring patient and public understanding of overtesting and overdiagnosis. We searched Scopus, CINAHL, Ovid MEDLINE and PsycINFO databases from inception to March 18, 2020. We included published English-language primary studies exploring the perspectives of patients/the public about overtesting/overdiagnosis from any setting, year and relating to any condition. Only qualitative parts of mixed-methods studies were synthesised. We excluded studies that only examined overtreatment or sampled people with specialised medical knowledge. Two authors independently selected studies, extracted data, assessed the methodological quality of included studies using the CASP tool, and assessed confidence in the synthesis findings using the GRADE-CERQual approach. Data was analysed using thematic meta-synthesis, utilising descriptive and interpretive methods. We synthesised data from 21 studies, comprising 1638 participants, from 2754 unique records identified. We identified six descriptive themes, all graded as moderate confidence (indicating they are likely to reasonably represent the available evidence): i) high confidence in screening and testing; ii) difficulty in understanding overuse; iii) acceptance that overuse can be harmful; iv) rejection or problematisation of overuse; v) limited impacts of overuse information on intended test and screening uptake; vi) desire for information and shared decision-making regarding overuse. The descriptive themes were underpinned by two analytic themes: i) perceived intrinsic value of information and information gathering, and; ii) differences in comprehension and acceptance of overuse concepts. This study identified novel and important insights about how lay people interpret overuse concepts. It will guide the development of more effective public messages about overuse, highlighting the importance of interpretative frameworks in these communications.


Diffusiophoresis of active colloids in viscoelastic media.
Self-diffusiophoresis of synthetic Janus (Si/Pt) microspheres in the presence of hydrogen peroxide in complex environments is here investigated. We aim to address the single particle dynamics of these active colloids in different viscoelastic fluids. Experimentally, the Janus colloids were dispersed in a dilute polyvinylpyrrolidone (PVP) solution and in a polyacrylamide (PAM) solution in semi-dilute and semi-dilute entangled regime to analyze their Brownian and active motion. These two systems were chosen to probe different relaxation times from relatively short (∼5 ms) for PVP to large (∼14.5 s) for PAM but always smaller than the rotary Brownian motion time scale. Within this regime, we investigate the coupling between the self-propulsion velocity and the medium rheology. Janus particles are found to get physically confined by polymeric entanglements but surprisingly they are able to escape the physical cage in a time scale much shorter than the relaxation time of the polymer solution. This is particularly relevant for application of self-propelling particles in biomedicine, water and soil remediation where complex environments are naturally present.


Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study.
Few studies have investigated whether ethnic groups differ in the prevalence of peripheral arterial disease (PAD). We compared the distribution of the ankle-brachial index (ABI), a measure of PAD, between African Americans and non-Hispanic white individuals. Subjects (n = 931) belonged to the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a community-based study of hypertensive sibships, and included 453 African Americans from Jackson, Mississipi (mean age 72 +/- 6 years, 69% women) and 478 non-Hispanic white individuals from Rochester, Minnesota (mean age 58 +/- 7 years, 64% women). ABI was determined at two sites in each lower extremity and the lowest of four indices was used in the analyses. PAD was defined as an ABI of < or = 0.95. Information about conventional risk factors was derived from interviews and from blood samples drawn at the study visit. The prevalence of diabetes and hypertension was significantly higher in African Americans than in non-Hispanic white individuals. After adjusting for age, African American subjects had a lower mean ABI (women 0.97 vs 1.04, p < 0.001; men 0.96 vs 1.12, p < 0.001) and a greater prevalence of PAD (women 34% vs 22%, p = 0.010; men 33% vs 11%, p < 0.001) than their non-Hispanic white counterparts. In multiple regression analyses, African American ethnicity was a predictor of a lower ABI and the presence of PAD in each sex after adjusting for age and other conventional risk factors. In conclusion, the lower ABI and greater prevalence of PAD in African Americans than in non-Hispanic white individuals is not explained by differences in conventional risk factors. Identifying additional 'novel' risk factors that account for the ethnic differences in PAD is an important next step towards understanding why such differences exist and developing more effective strategies to reduce the burden of PAD.


Pilates-based therapeutic exercise for pregnancy-related low back and pelvic pain: A prospective, randomized, controlled trial.
In this study, we aimed to clarify the impact of a Pilates-based therapeutic exercise on disability, pain, mood, and sleep quality in patients with pregnancy-related lumbopelvic pain (LPP). In the single-blinded randomized controlled study conducted between January 2018 and June 2018, 34 pregnant women (mean age: 29.7±6.2 years; range, 18 to 40 years) in the second trimester (week 14-24) with LPP were randomly assigned to a control group and a Pilates group. All patients underwent usual prenatal care. In addition, the selected Pilates exercise was carried out twice a week for 60-min per session for 12 weeks in the Pilates group. The control group was not prescribed an exercise regimen; however, they were not discouraged from exercising. The primary outcome was disability; secondary outcomes were LPP, mood, and sleep quality. Disability [Roland-Morris Disability Questionnaire (RMDQ)], LPP [Visual Analog Scale (VAS)], mood [Hospital Anxiety and Depression Scale, Anxiety (HADS-A) and Depression (HADS-D) subscales], and sleep quality [Pittsburgh Sleep Quality Index (PSQI)] were measured before and after 12 weeks. Adverse effects and adherence were recorded to determine exercise safety and compliance. The intention-to-treat analysis was applied. The between-group effect sizes were moderate for the RMDQ and VAS scales (d=0.4 and d=0.7, respectively) and small for the HADS-A and HADS-D scales (both d=0.2). The intention-to-treat analysis demonstrated that there was a statistically significant difference in disability, pain, and mood in favor of the Pilates group (p0.05). Adding Pilates to usual prenatal care should be considered a promising treatment option for pregnancy-related LPP.


Transition between frictional slip and ductile flow for halite shear zones at room temperature.
A complete transition from frictional slip to ductile shearing flow upon decreasing velocity (or slip rate) or increasing confining pressure is documented for a thin layer of halite undergoing large shearing deformation. The results indicate that the logarithmic law for steady-state friction with a negative velocity dependence breaks down when friction becomes nearly equal to the shear resistance required for ductile flow and that the law changes into a flow law in shear upon further decrease in velocity. The frictionvelocity relation is crucial in stability analyses of fault motion, and the results are important for earthquake and state-of-stress problems, especially in the application of laboratory data to the slow average motion of natural faults and to the behavior of deep faults along which ductile deformation becomes increasingly predominant.


Bacillus subtilis DNA polymerase III is required for the replication of DNA of bacteriophages SPP-1 and phi 105.
The replication of the Bacillus subtilis bacteriophages SPP-1 and phi 105 is sensitive to 6-(p-hydroxyphenylazo)-uracil (HPUra), a selective inhibitor of replicative DNA synthesis of B. subtilis which acts specifically at the levels of a replication-specific polymerase, DNA polymerase III (pol III). The origin of the HPUra-sensitive polymerase required for phage replication was examined by comparison of the drug sensitivity of phage development in a normosensitive host with that in a host carrying azp-12, a polC mutation that specifies production of an HPUra-resistant pol III. azp-12 specified HPUra-resistant phage host pol III. The host polIII requirement for SPP-1 replication also was confirmed by the demonstration that phage development was temperature sensitive in a host mutant carrying the polC mutation mut-1 (ts). Examination of the pol III activity of crude and purified cell-free preparations derived from phage-infected cells did not indicate any detectable changes in the specific activity, purification behavior, or drug sensitivity of the enzyme.


Simulated cuspal deflection and flexural properties of high viscosity bulk-fill and conventional resin composites.
The purpose of this study was to investigate the simulated cuspal deflection and flexural properties of high viscosity bulk-fill and conventional resin composites. Seven high viscosity bulk-fill resin composites and eight conventional resin composites were used. Aluminum blocks (10 mm x 8 mm x 15 mm) with a mesio-occlusal-distal (MOD) cavity [4 (W) mm x 8 (L) mm x 4 (D) mm] were prepared and randomly divided into groups for different measurement techniques [micrometer vs CSLM] and further subdivided according to type of resin composite (high viscosity bulk-fill vs conventional resin composite). The simulated cuspal deflection resulting from the polymerization of resin composite bonded to a precisely machined MOD cavity within an aluminum block was measured with either a novel highly accurate submicron digimatic micrometer (MDH-25 M, Mitsutoyo, Tokyo, Japan) or a confocal laser scanning microscope (CLSM, VK-9710, Keyence, Tokyo, Japan) cuspal measurement method. In addition, flexural properties of tested resin composites were measured to investigate the relationship between simulated cuspal deflection and flexural properties. Scanning electron microscopy observation of tested resin composites was also conducted. The simulated cuspal deflection of high viscosity bulk-fill resin composites was similar to that of conventional resin composites, regardless of measurement method. There were no statistically significant differences (p > 0.05) between the micrometer and CLSM cuspal measurement methods. There were statistically significant differences (p < 0.05) in flexural strength and elastic modulus depending on the material, regardless of the type of resin composite. Pearson correlation analysis did not show any statistically significant (p < 0.05) relationship between flexural properties and cuspal deflection. The results of this study indicate that high viscosity bulk-fill resin composites show similar cuspal deflection with bulk-filling techniques, to those shown by conventional resin composites with incremental filling techniques. Simulated cuspal deflection can be measured using either a micrometer or CLSM, but this experiment failed to show any relationship between the flexural properties and simulated cuspal deflection of resin composites. High viscosity bulk-fill resin composites produce the same level of cuspal deflection as a conventional incrementally filled resin composite.


Evaluation of the Parasight Platform for Malaria Diagnosis.
The World Health Organization estimates that nearly 500 million malaria tests are performed annually. While microscopy and rapid diagnostic tests (RDTs) are the main diagnostic approaches, no single method is inexpensive, rapid, and highly accurate. Two recent studies from our group have demonstrated a prototype computer vision platform that meets those needs. Here we present the results from two clinical studies on the commercially available version of this technology, the Sight Diagnostics Parasight platform, which provides malaria diagnosis, species identification, and parasite quantification. We conducted a multisite trial in Chennai, India (Apollo Hospital [n = 205]), and Nairobi, Kenya (Aga Khan University Hospital [n = 263]), in which we compared the device to microscopy, RDTs, and PCR. For identification of malaria, the device performed similarly well in both contexts (sensitivity of 99% and specificity of 100% at the Indian site and sensitivity of 99.3% and specificity of 98.9% at the Kenyan site, compared to PCR). For species identification, the device correctly identified 100% of samples with Plasmodium vivax and 100% of samples with Plasmodium falciparum in India and 100% of samples with P. vivax and 96.1% of samples with P. falciparum in Kenya, compared to PCR. Lastly, comparisons of the device parasite counts with those of trained microscopists produced average Pearson correlation coefficients of 0.84 at the Indian site and 0.85 at the Kenyan site.


Public T cell receptors confer high-avidity CD4 responses to HIV controllers.
The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.


Transition in Older Parent-Adult Child Relations in U.S. Chinese Immigrant Families.
The family fundamentally underpins the immigration and acculturation processes. But most existing research on acculturation focuses on individual instead of family experience. Guided by Berry's acculturation theory and Intergenerational Solidarity Theory, this study examined continuity and changes in parent-adult child relations of older Chinese immigrants over a 2-year period, and their implications for older adults' depression and quality of life (QoL). Participants included 2,605 older Chinese immigrants from the Population Study of Chinese Elderly in Chicago (PINE). Latent Transition Analysis (LTA) was used to identify transitions in multidimensional parent-child relations over time. Negative binomial and logistic regressions were used to examine the influence of family transitions on depression and QoL, respectively. LTA revealed five types of family relations: traditional, modified traditional, coresiding-unobligated, independent, and detached. Over 40% of the respondents shifted to a different relation type, with more families classified as modified traditional or independent over time. Transitioning into modified traditional relations or out of detached relations was associated with fewer depressive symptoms and better QoL at the follow-up. Transitioning into independent relation was associated with more depressive symptoms over time. Parent-child relations among Chinese older immigrants demonstrate significant complexity, including both heterogeneity and fluidity. Better well-being of these older adults seems to stem from the optimal combination of retaining the supportive heritage culture and embracing the host society's instrumental cultural elements. Services to this population need to include the family context in assessment and interventions.


DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain.
The present study documents the existence in mammalian brain of a phosphoprotein which may play a biological role in dopaminoceptive neurons. This protein has been designated DARPP-32 (dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein-32,000). The regional distribution of DARPP-32 in the rat brain follows the general pattern of dopaminergic innervation. DARPP-32 is present in dopaminoceptive rather than dopaminergic neurons. Moreover, it appears to be concentrated in a subpopulation of dopaminoceptive cells, namely those containing D-1 receptors (dopamine receptors coupled to adenylate cyclase activation), where it is localized in cell bodies, dendrites, axons, and nerve terminals. DARPP-32 is phosphorylated in intact cells from the caudatoputamen by dopamine and by 8-bromo-cyclic adenosine 3':5'-monophosphate and in cell-free preparations by cyclic adenosine 3':5'-monophosphate-dependent protein kinase. In two accompanying papers, we report the purification and biochemical characterization of DARPP-32 (Hemmings, H.C., Jr., A.C. Nairn, D.W. Aswad, and P. Greengard (1984) J. Neurosci. 4: 99-110) and the immunocytochemical localization of this phosphoprotein (Ouimet, C.C., P. Miller, H.C. Hemmings, Jr., S.I. Walaas, and P. Greengard (1984) J. Neurosci. 4: 111-124).


Large-scale CFD simulations of the transitional and turbulent regime for the large human airways during rapid inhalation.
The dynamics of unsteady flow in the human large airways during a rapid inhalation were investigated using highly detailed large-scale computational fluid dynamics on a subject-specific geometry. The simulations were performed to resolve all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code was used, running on two supercomputers, solving the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations and wall shear stresses on a rapid and short inhalation (a so-called sniff). The geometry used encompasses the exterior face and the airways from the nasal cavity, through the trachea and up to the third lung bifurcation; it was derived from a contrast-enhanced computed tomography (CT) scan of a 48-year-old male. The transient inflow produces complex flows over a wide range of Reynolds numbers (Re). Thanks to the high fidelity simulations, many features involving the flow transition were observed, with the level of turbulence clearly higher in the throat than in the nose. Spectral analysis revealed turbulent characteristics persisting downstream of the glottis, and were captured even with a medium mesh resolution. However a fine mesh resolution was found necessary in the nasal cavity to observe transitional features. This work indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow also has implications for the design of interventions such as aerosol drug delivery.


Readability and comprehensibility of informed consent forms for clinical trials.
The signed informed consent form provides documentary evidence that the patient has given informed consent to participate in a clinical trial and that the patient has been given the requisite information. However, this document must not only provide the necessary information, it must also be provided in a way that can be understood by the patient. Non conclusive information suggests that research participants frequently may not understand the information presented during the informed consent procedure. Comprehension requires that the patient be able to understand the information presented and have the time and opportunity to read, evaluate and consider the information presented.A shortened Informed Consent Form, with information that a reasonable person would want to understand along with specific information that the person wants in particular would be a good option to improve understanding or comprehensibility. Additional informational meetings with a qualified person like a counselor could help in comprehension. Questionnaires designed to test comprehension of patient, peer review, patient writing the salient features could help evaluate the comprehensibility of the Informed Consent Form.


Extended-spectrum beta-lactamases.
Resistance to broad-spectrum cephalosporins among Klebsiella pneumoniae has increased significantly, particularly in the intensive care unit setting, in the past decade. The problem has been noted not only in the United States, but around the world. A major mechanism responsible for this is the emergence of extended-spectrum beta-lactamases (ESBLs). These plasmid-mediated beta-lactamases confer resistance to broad-spectrum beta-lactam antibiotics, including third- and fourth-generation cephalosporins, aztreonam, and extended-spectrum penicillins. Other resistances, such as aminoglycoside and trimethoprim-sulfamethoxazole resistance, are often cotransferred on the same plasmid. Fluoroquinolone resistance is also frequently associated, resulting in an organism resistant to most broad-spectrum options. The carbapenems are currently considered the drug of choice for these pathogens. Prevention and control measures are important because of the multiresistant nature of these pathogens. Such traditional infection control measures as contact precautions are recommended. In addition, because this type of antimicrobial resistance appears to be particularly influenced by antibiotic use, antibiotic control measures may also be a very important intervention in controlling the spread of ESBLs.


Absenteeism amongst health workers--developing a typology to support empiric work in low-income countries and characterizing reported associations.
The contribution of inadequate health worker numbers and emigration have been highlighted in the international literature, but relatively little attention has been paid to absenteeism as a factor that undermines health-care delivery in low income countries. We therefore aimed to review the literature on absenteeism from a health system manager's perspective to inform needed work on this topic. Specifically, we aimed to develop a typology of definitions that might be useful to classify different forms of absenteeism and identify factors associated with absenteeism. Sixty-nine studies were reviewed, only four were from sub-Saharan Africa where the human resources for health crisis is most acute. Forms of absenteeism studied and methods used vary widely. No previous attempt to develop an overarching approach to classifying forms of absenteeism was identified. A typology based on key characteristics is proposed to fill this gap and considers absenteeism as defined by two key attributes, whether it is: planned/unplanned, and voluntary/involuntary. Factors reported to influence rates of absenteeism may be broadly classified into three thematic categories: workplace and content, personal and organizational and cultural factors. The literature presents an inconsistent picture of the effects of specific factors within these themes perhaps related to true contextual differences or inconsistent definitions of absenteeism.


The Influence of Surface Topography and Wettability on Escherichia coli Removal from Polymeric Materials in the Presence of a Blood Conditioning Film.
The reduction of biofouling and the reduction of cross-contamination in the food industry are important aspects of safety management systems. Polymeric surfaces are used extensively throughout the food production industry and therefore ensuring that effective cleaning regimes are conducted is vital. Throughout this study, the influence of the surface characteristics of three different polymeric surfaces, polytetrafluoroethylene (PTFE), poly(methyl methacrylate) (PMMA) and polyethylene terephthalate (PET), on the removal of Escherichia coli using a wipe clean method utilising 3% sodium hypochlorite was determined. The PTFE surfaces were the roughest and demonstrated the least wettable surface (118.8°), followed by the PMMA (75.2°) and PET surfaces (53.9°). Following cleaning with a 3% sodium hypochlorite solution, bacteria were completely removed from the PTFE surfaces, whilst the PMMA and PET surfaces still had high numbers of bacteria recovered (1.2 × 107 CFU/mL and 6.3 × 107 CFU/mL, respectively). When bacterial suspensions were applied to the surfaces in the presence of a blood conditioning film, cleaning with sodium hypochlorite demonstrated that no bacteria were recovered from the PMMA surface. However, on both the PTFE and PET surfaces, bacteria were recovered at lower concentrations (2.0 × 102 CFU/mL and 1.3 × 103 CFU/mL, respectively). ATP bioluminescence results demonstrated significantly different ATP concentrations on the surfaces when soiled (PTFE: 132 relative light units (RLU), PMMA: 80 RLU and PET: 99 RLU). Following cleaning, both in the presence and absence of a blood conditioning film, all the surfaces were considered clean, producing ATP concentrations in the range of 0-2 RLU. The results generated in this study demonstrated that the presence of a blood conditioning film significantly altered the removal of bacteria from the polymeric surfaces following a standard cleaning regime. Conditioning films which represent the environment where the surface is intended to be used should be a vital part of the test regime to ensure an effective disinfection process.


Extraplacental transfer of water in the sheep.
1. Ten pregnant ewes were operated on at 130 days of gestation. The fetal trachea was intubated with a double-lumen tube, an inflatable occluder was placed around the umbilical cord, vascular catheters were placed in the fetal carotid artery and jugular vein and in the maternal jugular vein, and multiple catheters were placed in the amniotic and allantoic sacs. 2. At 139 days gestation, the fetus was ventilated in utero, and the umbilical cord was occluded. The extrafetal fluids were circulated by means of roller pumps. Known activities of radio-iodinated human serum albumin, tritium-labelled water and 14C-labelled urea were injected into the amniotic and/or allantoic fluids. Samples were obtained at 30 min intervals for several hours. 3. Extrafetal fluid volumes were calculated from the albumin distribution volumes. The amounts of labelled water transferred to the maternal circulation were calculated from the changes in tracer concentrations in extrafetal fluids and fetal plasma. 4. No labelled albumin was detected in fetal or maternal plasma. The permeability-surface area product of labelled water at the combined amniotic and allantoic interfaces with the ewe was 28.2 +/- 2.8 ml/min (mean +/- S.E.M.). In five preparations the values could be separately calculated for amniotic and allantoic interfaces. The two mean values (19 +/- 4 and 12 +/- 1 ml/min) were not significantly different from each other. The permeability-surface area product at the combined interfaces with the fetus was 0.96 +/- 0.17 ml/min. Urea was so much less permeable than water that no reliable permeability-surface area products could be calculated in all of the preparations. 5. We calculated that the hydraulic conductivity of the combined extraplacental pathway is more than 0.5% of that of the placenta. Because the osmotic gradient across the extraplacental pathway is one to two orders of magnitude greater than that across the placenta, extraplacental transfer of water can significantly affect intrauterine water volume.


Incidence and Operative Factors Associated With Discretional Postoperative Mechanical Ventilation After General Surgery.
Mechanical ventilation after general surgery is associated with worse outcomes, prolonged hospital stay, and increased health care cost. Postoperatively, patients admitted to the intensive care unit (ICU) may be categorized into 1 of 3 groups: extubated patients (EXT), patients with objective medical indications to remain ventilated (MED), and patients not meeting these criteria, called "discretional postoperative mechanical ventilation" (DPMV). The objectives of this study were to determine the incidence of DPMV in general surgery patients and identify the associated operative factors. At a large, tertiary medical center, we reviewed all surgical cases performed under general anesthesia from April 1, 2008 to February 28, 2015 and admitted to the ICU postoperatively. Patients were categorized into 1 of 3 cohorts: EXT, MED, or DPMV. Operative factors related to the American Society of Anesthesiologists Physical Status (ASA PS), duration of surgery, surgery end time, difficult airway management, intraoperative blood and fluid administration, vasopressor infusions, intraoperative arterial blood gasses, and ventilation data were collected. Additionally, anesthesia records were reviewed for notes indicating a reason or rationale for postoperative ventilation. Categorical variables were compared by χ test, and continuous variables by analysis of variance or Kruskal-Wallis H test. Categorical variables are presented as n (%), and continuous variables as mean ± standard deviation or median (interquartile range) as appropriate. Significance level was set at P≤ .05. Sixteen percent of the 3555 patients were categorized as DPMV and 12.2% as MED. Compared to EXT patients, those classified as DPMV had received significantly less fluid (2757 ± 2728 mL vs 3868 ± 1885 mL; P < .001), lost less blood during surgery (150 [20-625] mL vs 300 [150-600] mL; P< .001), underwent a shorter surgery (199 ± 215 minutes vs 276 ± 143 minutes; P< .001), but received more blood products, 900 (600-1800) mL vs 600 (300-900) mL. The DPMV group had more patients with high ASA PS (ASA III-V) than the EXT group: 508 (90.4%) vs 1934 (75.6%); P< .001. Emergency surgery (ASA E modifier) was more common in the DPMV group than the EXT group: 145 (25.8%) vs 306 (12%), P< .001, respectively. Surgery end after regular working hours was not significantly higher with DPMV status compared to EXT. DPMV cohort had fewer cases with difficult airway when compared to EXT or MED. When compared to MED patients, those classified as DPMV received less fluid (2757 ± 2728 mL vs 4499 ± 2830 mL; P< .001), lost less blood (150 [20-625] mL vs 500 [200-1350] mL; P < .001), but did not differ in blood products transfused or duration of surgery. In our tertiary medical center, patients often admitted to the ICU on mechanical ventilation without an objective medical indication. When compared to patients admitted to the ICU extubated, those mechanically ventilated but without an objective indication had a higher ASA PS class and were more likely to have an ASA E modifier. A surgery end time after regular working hours or difficult airway management was not associated with higher incidence of DPMV.