Transforming growth factor production by chemically transformed cells.
Evidence is presented indicating that the chemically transformed AKR-MCA and C3H/MCA-58 murine cell lines produce "transforming growth factor(s)" capable of inducing a transformed morphology and the ability to grow in soft agar in nontransformed, anchorage-dependent indicator cells. Serum-free medium conditioned by exposure to the chemically transformed cells was chromatographed on a Bio-Gel P-60 column after dialysis and lyophilization. Using the nontransformed mouse AKR-2B cells as the indicator cells, a peak of soft agar growth-stimulating activity was detected in the molecular weight range of 10,000 to 12,000. The soft agar growth-stimulating activity in pooled fractions from the AKR-MCA cells was shown to be trypsin and dithiothreitol sensitive and relatively heat stable; the activity was not destroyed by heating to 56 degrees for 30 min or to 100 degrees for 3 min. The pooled material also caused stimulation of growth in the soft agar of rat NRK cells and stimulation of DNA synthesis in the AKR-2B cells. The quantity required to give significant competition for binding to the epidermal growth factor receptor was about one order of magnitude greater than that required for stimulation of soft agar growth. Further separation of these polypeptide(s) by carboxymethylcellulose chromatography revealed three apparent peaks of soft agar growth-stimulating activity. Epidermal growth factor receptor-competing activity cochromatographed with the early minor soft agar growth-stimulating peak, whereas the two major peaks of soft agar growth-stimulating activity had no associated detectable competition for epidermal growth factor binding to its receptor. The data indicate that at least a major portion of the transforming growth factors produced by the chemically transformed cells is different from those described previously in murine sarcoma virus-transformed mouse cells and human tumor cells.


Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia.
Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.


Increased expression of glucagon-like peptide-1 receptors in psoriasis plaques.
Recent case reports suggest that treatment with glucagon-like peptide-1 (GLP-1) agonists results in clinical improvement of psoriasis. The purpose of this study was to determine whether GLP-1 receptors (GLP-1Rs) are found in the skin of healthy volunteers and psoriasis patients and if so, whether GLP-1Rs are located on keratinocytes or immune cells. Three mm-punch skin biopsies were taken for gene expression analysis from six healthy volunteers and from affected and unaffected skin of six psoriasis patients. In addition, a blood sample was obtained from all participants. Cultured human keratinocytes were either untreated or incubated with tumor necrosis factor- α (TNF-α), interferon-γ (IFN-γ) or a combination of TNF-α and IFN-γ for 48 h. Total RNA was extracted from all the samples, reversely transcribed and analysed for the expression of GLP-1R using real-time PCR. Gene expression analysis showed expression of GLP-1Rs in five of six skin biopsies from psoriasis plaques, in one of six biopsies from unaffected psoriatic skin and in one of six biopsies from healthy skin. GLP-1R expression was found in the blood of both healthy volunteers and psoriasis patients. No GLP-1R expression was found in either stimulated or unstimulated cultured human keratinocytes. Our results show increased presence of GLP-1Rs in psoriasis plaques and that this most likely is due to infiltration with immune cells. This offers a possible explanation for the positive effect of treatment with GLP-1R agonists in patients with psoriasis.


Blockchain Implementation in Health Care: Protocol for a Systematic Review.
A blockchain is a digitized, decentralized, distributed public ledger that acts as a shared and synchronized database that records cryptocurrency transactions. Despite the shift toward digital platforms enabled by electronic medical records, demonstrating a will to reform the health care sector, health systems face issues including security, interoperability, data fragmentation, timely access to patient data, and silos. The application of health care blockchains could enable data interoperability, enhancement of precision medicine, and reduction in prescription frauds through implementing novel methods in access and patient consent. To summarize the evidence on the strategies and frameworks utilized to implement blockchains for patient data in health care to ensure privacy and improve interoperability and scalability. It is anticipated this review will assist in the development of recommendations that will assist key stakeholders in health care blockchain implementation, and we predict that the evidence generated will challenge the health care status quo, moving away from more traditional approaches and facilitating decision making of patients, health care providers, and researchers. A systematic search of MEDLINE/PubMed, Embase, Scopus, ProQuest Technology Collection and Engineering Index will be conducted. Two experienced independent reviewers will conduct titles and abstract screening followed by full-text reading to determine study eligibility. Data will then be extracted onto data extraction forms before using the Cochrane Collaboration Risk of Bias Tool to appraise the quality of included randomized studies and the Risk of Bias in nonrandomized studies of Interventions to assess the quality of nonrandomized studies. Data will then be analyzed and synthesized. Database searches will be initiated in September 2018. We expect to complete the review in January 2019. This review will summarize the strategies and frameworks used to implement blockchains in health care to increase data privacy, interoperability, and scalability. This review will also help clarify if the strategies and frameworks required for the operationalization of blockchains in health care ensure the privacy of patient data while enabling efficiency, interoperability, and scalability. PRR1-10.2196/10994.


Discharge planning from hospital to home.
Discharge planning is a routine feature of health systems in many countries. The aim of discharge planning is to reduce hospital length of stay and unplanned readmission to hospital, and improve the co-ordination of services following discharge from hospital. To determine the effectiveness of planning the discharge of patients moving from hospital. We updated the review using the Cochrane EPOC Group Trials Register, MEDLINE, EMBASE and the Social Science Citation Index (last searched in March 2009). Randomised controlled trials (RCTs) that compared an individualised discharge plan with routine discharge care that was not tailored to the individual patient. Participants were hospital inpatients. Two authors independently undertook data analysis and quality assessment using a predesigned data extraction sheet. Studies are grouped according to patient group (elderly medical patients, surgical patients and those with a mix of conditions) and by outcome. Twenty-one RCTs (7234 patients) are included; ten of these were identified in this update. Fourteen trials recruited patients with a medical condition (4509 patients), four recruited patients with a mix of medical and surgical conditions (2225 patients), one recruited patients from a psychiatric hospital (343 patients), one from both a psychiatric hospital and from a general hospital (97 patients), and the final trial recruited patients admitted to hospital following a fall (60 patients). Hospital length of stay and readmissions to hospital were significantly reduced for patients allocated to discharge planning (mean difference length of stay -0.91, 95% CI -1.55 to -0.27, 10 trials; readmission rates RR 0.85, 95% CI 0.74 to 0.97, 11 trials). For elderly patients with a medical condition (usually heart failure) there was insufficient evidence for a difference in mortality (RR 1.04, 95% CI 0.74 to 1.46, four trials) or being discharged from hospital to home (RR 1.03, 95% CI 0.93 to 1.14, two trials). This was also the case for trials recruiting patients recovering from surgery and a mix of medical and surgical conditions. In three trials patients allocated to discharge planning reported increased satisfaction. There was little evidence on overall healthcare costs. The evidence suggests that a structured discharge plan tailored to the individual patient probably brings about small reductions in hospital length of stay and readmission rates for older people admitted to hospital with a medical condition. The impact of discharge planning on mortality, health outcomes and cost remains uncertain.


Antibody-mediated status epilepticus: a retrospective multicenter survey.
In recent years, an increasing number of auto-antibodies (AB) have been detected in the CSF and serum of patients with new onset epilepsy. Some of these patients develop convulsive or nonconvulsive status epilepticus (AB-SE), necessitating intensive medical care and administration of multiple antiepileptic and immunomodulatory treatments of uncertain effectiveness. In this retrospective multicenter survey we aimed to determine the spectrum of gravity, the duration and the prognosis of the disorder. In addition, we sought to identify the antibodies associated with this condition, as well as determine whether there is a most effective treatment regime. 12 European Neurology University Clinics, with extensive experience in the treatment of SE patients, were sent a detailed questionnaire regarding symptoms and treatment of AB-SE patients. Seven centers responded positively, providing a total of 13 patients above the age of 16. AB-SE affects mainly women (12/13, 92%) with a variable age at onset (17-69 years, median: 25 years). The duration of the disease is also variable (10 days to 12 years, median: 2 months). Only the 3 oldest patients died (55-69 years). Most patients were diagnosed with anti NMDAR encephalitis (8/13) and had oligoclonal bands in the CSF (9/13). No specific treatment regimen (antiepileptic, immunomodulatory) was found to be clearly superior. Most of the surviving 10 patients (77%) recovered completely or nearly so within 2 years of index poststatus. AB-SE is a severe but potentially reversible condition. Long duration does not seem to imply fatal outcome; however, age older than 50 years at time of onset appears to be a risk factor for death. There was no evidence for an optimal antiepileptic or immunomodulatory treatment. A prospective multicenter study is warranted in order to stratify the optimal treatment algorithm, determine clear risk factors of unfavorable outcome and long-term prognosis.


A "splitting" look at chronic nonspecific lung disease (CNSLD): common features but diverse pathogenesis.
The term chronic nonspecific lung disease (CNSLD) was proposed by the Ciba Symposium in 1959 as an umbrella term grouping chronic bronchitis, asthma, emphysema and irreversible or persistent obstructive lung disease. However, it has only been widely used by proponents of the Dutch Hypothesis, which states that these diseases all result from a common genetic root and should be considered as one disease. A major reason for proposing this hypothesis in 1961 was that these different entities share some common features, especially airway hyperresponsiveness. Although not formally disproven, evidence is accumulating--and reviewed here--against this "one disease concept"; hence, common features should not necessarily imply a common pathogenesis. Overlap features are sufficiently frequent in clinical practice to cause problems for labelling patients within the scope of CNSLD. The term could still be used as a starting point for a "splitting approach", identifying a small number of important basic features in order to allow a more systematic use of established labels for diseases within CNSLD. Our proposal for labelling emphasizes a consistent use of asthma, emphysema and chronic obstructive pulmonary disease (COPD), but restricts the use of chronic bronchitis to those patients with chronic bronchial hypersecretion without chronic airways obstruction.


Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication.
DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.


Effect of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China: a modelling study.
When a new infectious disease emerges, appropriate case definitions are important for clinical diagnosis and for public health surveillance. Tracking case numbers over time is important to establish the speed of spread and the effectiveness of interventions. We aimed to assess whether changes in case definitions affected inferences on the transmission dynamics of coronavirus disease 2019 (COVID-19) in China. We examined changes in the case definition for COVID-19 in mainland China during the first epidemic wave. We used exponential growth models to estimate how changes in the case definitions affected the number of cases reported each day. We then inferred how the epidemic curve would have appeared if the same case definition had been used throughout the epidemic. From Jan 15 to March 3, 2020, seven versions of the case definition for COVID-19 were issued by the National Health Commission in China. We estimated that when the case definitions were changed, the proportion of infections being detected as cases increased by 7·1 times (95% credible interval [CrI] 4·8-10·9) from version 1 to 2, 2·8 times (1·9-4·2) from version 2 to 4, and 4·2 times (2·6-7·3) from version 4 to 5. If the fifth version of the case definition had been applied throughout the outbreak with sufficient testing capacity, we estimated that by Feb 20, 2020, there would have been 232 000 (95% CrI 161 000-359 000) confirmed cases in China as opposed to the 55 508 confirmed cases reported. The case definition was initially narrow and was gradually broadened to allow detection of more cases as knowledge increased, particularly milder cases and those without epidemiological links to Wuhan, China, or other known cases. These changes should be taken into account when making inferences on epidemic growth rates and doubling times, and therefore on the reproductive number, to avoid bias. Health and Medical Research Fund, Hong Kong.


Speed limit of the insulator-metal transition in magnetite.
As the oldest known magnetic material, magnetite (Fe3O4) has fascinated mankind for millennia. As the first oxide in which a relationship between electrical conductivity and fluctuating/localized electronic order was shown, magnetite represents a model system for understanding correlated oxides in general. Nevertheless, the exact mechanism of the insulator-metal, or Verwey, transition has long remained inaccessible. Recently, three-Fe-site lattice distortions called trimerons were identified as the characteristic building blocks of the low-temperature insulating electronically ordered phase. Here we investigate the Verwey transition with pump-probe X-ray diffraction and optical reflectivity techniques, and show how trimerons become mobile across the insulator-metal transition. We find this to be a two-step process. After an initial 300 fs destruction of individual trimerons, phase separation occurs on a 1.5±0.2 ps timescale to yield residual insulating and metallic regions. This work establishes the speed limit for switching in future oxide electronics.


Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology.
Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.


DNA-induced dimerization of the single-stranded DNA binding telomeric protein Pot1 from Schizosaccharomyces pombe.
Eukaryotic chromosome ends are protected from illicit DNA joining by protein-DNA complexes called telomeres. In most studied organisms, telomeric DNA is composed of multiple short G-rich repeats that end in a single-stranded tail that is protected by the protein POT1. Mammalian POT1 binds two telomeric repeats as a monomer in a sequence-specific manner, and discriminates against RNA of telomeric sequence. While addressing the RNA discrimination properties of SpPot1, the POT1 homolog in Schizosaccharomyces pombe, we found an unanticipated ssDNA-binding mode in which two SpPot1 molecules bind an oligonucleotide containing two telomeric repeats. DNA binding seems to be achieved via binding of the most N-terminal OB domain of each monomer to each telomeric repeat. The SpPot1 dimer may have evolved to accommodate the heterogeneous spacers that occur between S. pombe telomeric repeats, and it also has implications for telomere architecture. We further show that the S. pombe telomeric protein Tpz1, like its mammalian homolog TPP1, increases the affinity of Pot1 for telomeric single-stranded DNA and enhances the discrimination of Pot1 against RNA.


Ligand accumulation in autocrine cell cultures.
Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and analysis of experiments with autocrine cells, we develop a biophysical theory of ligand accumulation in cell-culture assays. Our theory predicts the ligand concentration as a function of time and measurable parameters of autocrine cells and cell-culture experiments. The key step of our analysis is the derivation of the survival probability of a single ligand released from the surface of an autocrine cell. An expression for this probability is derived using the boundary homogenization approach and tested by stochastic simulations. We use this expression in the integral balance equations, from which we find the Laplace transform of the ligand concentration. We demonstrate how the theory works by analyzing the autocrine epidermal growth factor receptor system and discuss the extension of our methods to other experiments with cultured autocrine cells.


Maintenance of HSC by Wnt5a secreting AGM-derived stromal cell line.
The microenvironment wherein hematopoietic stem cells (HSC) reside orchestrates HSC self-renewal vs. differentiation decisions. Stromal cells derived from ontogenically divergent hematopoietic microenvironments can support HSC in vitro and have been used to decipher factors that influence HSC fate decisions. Employing stromal cell lines derived from the aorta-gonad-mesonephros and embryonic liver, we aim to identify secreted factors that maintain/expand HSC in vitro. We cultured murine lineage antigen-negative (Lin(-)) bone marrow cells in transwells above the UG26-1B6, urogenital ridge-, and EL08-1D2, embryonic liver-derived cell lines. We, also, performed real-time quantitative PCR analysis to identify differentially expressed genes from the Wnt family of proteins in ontogenically different stromal cell lines. Lin(-) murine bone marrow cells maintained for 3 weeks in transwells above UG26-1B6 but not EL08-1D2 cells contained competitive repopulating HSC. Addition of as few as 25% UG26-1B6 cells to EL08-1D2 feeders led to maintenance of HSC in noncontact cultures, validating soluble factors are secreted by the UG26-1B6 cells. As we found that Wnt5a was significantly higher expressed in UG26-1B6 than EL08-1D2 cells, we added Wnt5a to EL08-1D2 transwell cultures or an antibody against Wnt5a to UG26-1B6 transwell cultures. Addition of Wnt5a to EL08-1D2 transwell cultures restored maintenance of HSC, whereas addition of an anti-Wnt5a antibody to UG26-1B6 transwell cultures inhibited maintenance of competitive repopulating HSC. We demonstrate that stromal cell lines generated from embryonic microenvironments provide a tool to identify secreted proteins that play a role in the maintenance of HSC, and that at least one of the factors produced by UG26-1B6 cells responsible for preserving HSC is Wnt5a.


The Contribution of In Vivo Mammalian Studies to the Knowledge of Adverse Effects of Radiofrequency Radiation on Human Health.
The proliferation of cellular antennas and other radiofrequency radiation (RFR) generating devices of the last decades has led to more and more concerns about the potential health effects from RFR exposure. Since the 2011 classification as a possible carcinogen by the International Agency for Research on Cancer (IARC), more experimental studies have been published that support a causal association between RFR exposure and health hazards. As regard cancer risk, two long-term experimental studies have been recently published by the US National Toxicology Program (NTP) and the Italian Ramazzini Institute (RI). Despite important experimental differences, both studies found statistically significant increases in the development of the same type of very rare glial malignant tumors. In addition to carcinogenicity, reproductive organs might be particularly exposed, as well as sensitive to RFR. In this work, we reviewed the currently available evidence from in vivo studies on carcinogenicity and reproductive toxicity studies in order to summarize the contribution of experimental research to the prevention of the adverse effects of RFR on human health.


Rules for generating conformers and their relative energies in n-alkanes with a heteroelement O or S: ethers and alcohols, or sulfides and thiols.
With the aid of density functional theory calculations, all conformers of several single-chain alcohols, thiols, ethers, and sulfides are investigated. Starting from earlier computational works on n-alkanes, we construct an extended set of general rules for predicting the number and occurrence of conformers in these oxygen- or sulfur-containing compounds. In alcohols and thiols, it is found that only the conformers generated by internal rotations in the HXCH(2)CH(2)CH(2) (X = O or S) top are distinctive from those in n-alkanes. In ethers and sulfides, the primary influence of the heteroelement also extends up to three internal rotations, but many more conformers are possible. However, a number of double gauche sequences are forbidden, and therefore, several conformers can be eliminated. These exclusions in particular make up a set of rules for eventually deducing all possible conformers. Furthermore, on the basis of only an exact calculation of these gg conformations in addition to single gauche conformers, it is possible to make an accurate estimate of the relative energy. This two-dimensional approximation scheme constitutes an effective tool for adequately describing the relative energies of all possible conformers at a minimal computational cost.


An oxo-bacteriochlorin derivative for long-wavelength fluorescence ratiometric alcohol sensing.
A fluorescent ratiometric optical chemical sensor (optode) for alcohol detection is presented. A lipophilized bacteriochlorin derivative possessing a trifluoroacetyl group at the 3-position was synthesized for alcohol detection. When embedded in a plasticized poly(vinyl chloride) (PVC) membrane, the fluororeceptor shows a significant signal change on exposure to aqueous ethanol solutions both in the absorbance and the fluorescence emission. This optode allows the determination of ethanol concentrations in aqueous sample solutions by ratiometric fluorometry. The fluorescent indicator responds with increasing fluorescence around 701 nm and decreasing fluorescence around 751 nm towards the presence of ethanol. The optode response was found to be fully reversible in a dynamic measurement range from 0.3% to at least 25% (v/v) ethanol. The limit of detection (LOD) and the limit of quantification (LOQ) of the sensor for ethanol were estimated to be 0.1% and 0.4% (v/v), respectively. These results indicate that the new optode can be employed as an ethanol-sensing device with high sensitivity for beverage and industrial analyses.


Piperlongumine chemosensitizes tumor cells through interaction with cysteine 179 of IκBα kinase, leading to suppression of NF-κB-regulated gene products.
Recently, two different reports appeared in prominent journals suggesting a mechanism by which piperlongumine, a pyridine alkaloid, mediates anticancer effects. In the current report, we describe another novel mechanism by which this alkaloid mediates its anticancer effects. We found that piperlongumine blocked NF-κB activated by TNFα and various other cancer promoters. This downregulation was accompanied by inhibition of phosphorylation and degradation of IκBα. Further investigation revealed that this pyridine alkaloid directly interacts with IκBα kinase (IKK) and inhibits its activity. Inhibition of IKK occurred through interaction with its cysteine 179 as the mutation of this residue to alanine abolished the activity of piperlongumine. Inhibition in NF-κB activity downregulated the expression of proteins involved in cell survival (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, survivin), proliferation (c-Myc, cyclin D1), inflammation (COX-2, IL6), and invasion (ICAM-1, -9, CXCR-4, VEGF). Overall, our results reveal a novel mechanism by which piperlongumine can exhibit antitumor activity through downmodulation of proinflammatory pathway.


Methane as a resource: can the methanotrophs add value?
Methane is an abundant gas used in energy recovery systems, heating, and transport. Methanotrophs are bacteria capable of using methane as their sole carbon source. Although intensively researched, the myriad of potential biotechnological applications of methanotrophic bacteria has not been comprehensively discussed in a single review. Methanotrophs can generate single-cell protein, biopolymers, components for nanotechnology applications (surface layers), soluble metabolites (methanol, formaldehyde, organic acids, and ectoine), lipids (biodiesel and health supplements), growth media, and vitamin B12 using methane as their carbon source. They may be genetically engineered to produce new compounds such as carotenoids or farnesene. Some enzymes (dehydrogenases, oxidase, and catalase) are valuable products with high conversion efficiencies and can generate methanol or sequester CO2 as formic acid ex vivo. Live cultures can be used for bioremediation, chemical transformation (propene to propylene oxide), wastewater denitrification, as components of biosensors, or possibly for directly generating electricity. This review demonstrates the potential for methanotrophs and their consortia to generate value while using methane as a carbon source. While there are notable challenges using a low solubility gas as a carbon source, the massive methane resource, and the potential cost savings while sequestering a greenhouse gas, keeps interest piqued in these unique bacteria.


Reprogramming efficiency and quality of induced Pluripotent Stem Cells (iPSCs) generated from muscle-derived fibroblasts of mdx mice at different ages.
Induced pluripotent stem cells (iPSCs) hold promise as a potential treatment for Duchenne muscular dystrophy (DMD). To determine the impact of the donor's age on reprogramming, we generated iPSCs from muscle-derived fibroblasts (MuFs) of mdx mice aged 6 weeks, 6 months, and 14 months. MuFs from 14-month-old mdx mice showed lower proliferative activity and lower reprogramming efficiency, compared with those from younger mdx mice. Furthermore, iPSCs derived from 14-month-old mdx mice (14m-MuF-iPSCs) gradually lost Nanog expression, and regressed in conventional ES medium during passages. Interestingly, inhibition of TGF-β signaling and BMP signaling stabilized Nanog expression and promoted self-renewal of 14m-MuF-iPSCs. Finally, rescued mdx-derived iPSCs efficiently differentiated into the skeletal muscle lineage.


Quality achievement and disease prevalence in primary care predicts regional variation in renal replacement therapy (RRT) incidence: an ecological study.
Diabetes Meillitus (DM) and hypertension (HT) are important causes of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is the standard active treatment. Financially, incentivized quality initiatives for primary care include pay-for-performance (P4P) in DM and HT. Our aim was to examine any effect of disease prevalence and P4P on RRT incidence and regional variation. The incidence of RRT, sex and ethnicity data and P4P disease register and achievement data were obtained for each NHS locality. We calculated correlation coefficients for P4P indicators since 2004/05 and socio-demographic data for these 152 localities. We then developed a regression model and regression coefficient (R(2)) to assess to what extent these variables might predict RRT incidence. Many of the P4P indicators were weakly but highly significantly correlated with RRT incidence. The strongest correlation was 2004/05 for DM prevalence and 2006/07 for HT quality. DM prevalence and the percentage with blood pressure control in HT target (HT quality) were the most predictive in our regression model R(2) = 0.096 and R(2) = 0.085, respectively (P < 0.001). Combined they predicted a fifth of RRT incidence (R(2) = 0.2, P < 0.001) while ethnicity and deprivation a quarter (R(2) = 0.25, P < 0.001). Our final model contained proportion of population >75 years, DM prevalence, HT quality, ethnicity and deprivation index and predicted 40% of variation (R(2) = 0.4, P < 0.001). Our findings add prevalence of DM and quality of HT management to the known predictors of variation in RRT, ethnicity and deprivation. They raise the possibility that interventions in primary care might influence later events in specialist care.


Efficient and Reliable Production of Vectors for the Study of the Repair, Mutagenesis, and Phenotypic Consequences of Defined DNA Damage Lesions in Mammalian Cells.
Mammalian cells are constantly and unavoidably exposed to DNA damage from endogenous and exogenous sources, frequently to the detriment of genomic integrity and biological function. Cells acquire a large number of chemically diverse lesions per day, and each can have a different genetic fate and biological consequences. However, our knowledge of how and when specific lesions are repaired or how they may compromise the fidelity of DNA replication or transcription and lead to deleterious biological endpoints in mammalian cells is limited. Studying individual lesions requires technically challenging approaches for the targeted introduction of defined lesions into relevant DNA sequences of interest. Here, we present a systematic analysis of factors influencing yield and an improved, efficient and reliable protocol for the production of mammalian expression phagemid vectors containing defined DNA base modifications in any sequence position of either complementary DNA strand. We applied our improved protocol to study the transcriptional mutagenesis-mediated phenotypic consequences of the common oxidative lesion 5-hydroxyuracil, placed in the G12 mutational hotspot of the KRAS oncogene. 5-OHU induced sustained oncogenic signaling in Neil1-/-Neil2-/- mouse cells. The resulting advance in technology will have broad applicability for investigation of single lesion DNA repair, mutagenesis, and DNA damage responses in mammalian cells.


Session Recommendation via Recurrent Neural Networks over Fisher Embedding Vectors.
Recommendation services bear great importance in e-commerce, shopping, tourism, and social media, as they aid the user in navigating through the items that are most relevant to their needs. In order to build recommender systems, organizations log the item consumption in their user sessions by using different sensors. For instance, Web sites use Web data loggers, museums and shopping centers rely on user in-door positioning systems to register user movement, and Location-Based Social Networks use Global Positioning System for out-door user tracking. Most organizations do not have a detailed history of previous activities or purchases by the user. Hence, in most cases recommenders propose items that are similar to the most recent ones viewed in the current user session. The corresponding task is called session based, and when only the last item is considered, it is referred to as item-to-item recommendation. A natural way of building next-item recommendations relies on item-to-item similarities and item-to-item transitions in the form of "people who viewed this, also viewed" lists. Such methods, however, depend on local information for the given item pairs, which can result in unstable results for items with short transaction history, especially in connection with the cold-start items that recently appeared and had no time yet to accumulate a sufficient number of transactions. In this paper, we give new algorithms by defining a global probabilistic similarity model of all the items based on Random Fields. We give a generative model for the item interactions based on arbitrary distance measures over the items, including explicit, implicit ratings and external metadata to estimate and predict item-to-item transition probabilities. We exploit our new model in two different item similarity algorithms, as well as a feature representation in a recurrent neural network based recommender. Our experiments on various publicly available data sets show that our new model outperforms simple similarity baseline methods and combines well with recent item-to-item and deep learning recommenders under several different performance metrics.


Non-monotonic auto-regulation in single gene circuits.
We theoretically study the effects of non-monotonic response curves in genetic auto-regulation by exploring the possible dynamical behaviors for such systems. Our motivation is twofold: we aim at conceiving the simplest genetic circuits for synthetic biology and at understanding the natural auto-regulation of the LrpB protein of the Sulfolobus solfataricus archaeon which exhibits non-monotonicity. We analyzed three toy models, based on mass-action kinetics, with increasing complexity and sought for oscillations and (fast) bistable switching. We performed large parameter scans and sensitivity analyses, and quantified the quality of the oscillators and switches by computing relative volumes in parameter space reproducing the sought dynamical behavior. All single gene systems need finely tuned parameters in order to oscillate, but bistable switches are more robust against parameter changes. We expected non-monotonic switches to be faster than monotonic ones, however solutions combining both auto-activation and repression in the physiological range to obtain fast switches are scarce. Our analysis shows that the Ss-LrpB system can not provide a bistable switch and that robust oscillations are unlikely. Gillespie simulations suggest that the function of the natural Ss-LrpB system is sensing via a spiking behavior, which is in line with the fact that this protein has a metabolic regulatory function and binds to a ligand.


miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5.
Purpose: miR-196b-5p has been previously implicated in malignant transformation; however, its role in colorectal cancer has not been fully explored. In this study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in colorectal cancer.Experimental Design: miR-196b-5p expression was quantitated by qRT-PCR in 2 independent cohorts composed of 292 patients with colorectal cancer in total, to explore its biomarker potential. Transient and stable gain- and loss-of-function experiments were conducted in a panel of colorectal cancer cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemosensitivity, migration/invasion, and metastases formation in vitro and in vivo The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in silico target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments.Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (P < 0.05, log-rank test). miR-196b-5p inhibition led to significantly increased colorectal cancer cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulated colorectal cancer cell migration.Conclusions: The association of low levels of miR-196b-5p and poor prognosis in patients with colorectal cancer can be explained by its influence on cancer cell migration and metastases formation. miR-196b-5p has an impact on colorectal cancer progression pathways through direct interaction with genes involved in cancer cell migration. Clin Cancer Res; 23(17); 5255-66. ©2017 AACR.


Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia.
There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.


The transcription factor GATA-6 regulates pathological cardiac hypertrophy.
The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown. To determine the role of GATA-6 in cardiac hypertrophy and homeostasis. Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload-induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes. These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4.


[Critical appraisal of sevelamer for the treatment of hyperphosphatemia in patients with chronic renal failure].
To evaluate in patients with chronic renal failure (CRF) the effectiveness and the costs of sevelamer, a cationic polymer calcium- and aluminum-free, that is a new gastrointestinal phosphate binder. Literature review and critical appraisal of six clinical trials about the effectiveness and two economic studies of sevelamer in CRF patients. Sevelamer is an effective phosphate binder (used in a mean daily dose of 3.5 g three times per day with meals) and with similar effect as that obtained with calcium salts, without the adverse manifestations of the latter (elevation of calcium x phosphorus product, hypercalcemia, vascular and cardiac calcifications, etc.). Moreover, sevelamer reduced serum LDL cholesterol in around 30%. Despite the greater direct costs of sevelamer compared with calcium salts, the total costs may be lower due to the reduction of costs with clinical complications and hospitalizations. Sevelamer has important therapeutic value in CRF patients with hyperphosphatemia. Economic analyses should be performed in our setting to define the cost-effectiveness relationship of sevelamer.


'It puts life in us and we feel big': shifts in the local health care system during the introduction of rapid diagnostic tests for malaria into drug shops in Uganda.
This paper is an analysis of the social interaction between drug sellers, their clients and local health care workers within a medical trial that introduced rapid diagnostic tests for malaria into private sector drug shops in Mukono District, Uganda. It locates the introduction of a new technology to test blood and a system of referral within the context of local concerns about the choice and evaluation of treatment; and the socially legitimated statuses, roles and hierarchies within the local health care system. Based on the multi-layered interpretation of 21 focus group discussions, we describe three key aspects of the trial central to local interpretation: openly testing blood, supervisory visits to drug shops and a new referral form. Each had the potential to shift drug shop vendors from outsider to insider of the formal health service. The responses of the different groups of participants reflect their situation within the health care system. The clients and patients welcomed the local availability of new diagnostic technology and the apparent involvement of the government in securing good quality health services for them from providers with often uncertain credentials. The drug shop vendors welcomed the authorization to openly test blood, enabling the demonstration of a new skill and newfound legitimacy as a health worker rather than simple drug seller. Formal sector health workers were less enthusiastic about the trial, raising concerns about professional hierarchies and the maintenance of a boundary around the formal health service to ensure the exclusion of those they considered untrained, unprofessional and untrustworthy personnel.


Modelling youth pregnancy in continental Portugal through geographically weighted regression.
Youth pregnancy, a global public health problem with important social, educational and economic impact, has mostly been studied in the least developed countries. However, this condition also affects the industrialized countries. This article presents a youth pregnancy study at the municipality level in continental Portugal based on geographically weighted regression. The results indicate that youth pregnancy rates can be explained by several variables: i) proportion (%) of social security beneficiaries; ii) number of households without amenities; iii) the rate of those prematurely leaving school; iv) the unemployment rates of youths and females, ceteris paribus. In addition, it was found that the beneficiaries of social security had a higher impact on youth pregnancy in the southern part of the country, and in the Centre too; that households without amenities had a higher impact along the central coast and in the South; that rates of those leaving school prematurely had a higher influence in the North and the Interior than in the rest of the country; and that youth and female unemployment rates were more widespread in the Centre, particularly along the coast. Overall, the model identified a strong association of explanatory variables with youth pregnancy rates in the country as a whole, except in the Porto metropolitan area. These findings may help health planners to define policies to mitigate this important social problem.


Resolution of Thumb Pain following Adoption of Mathieu Needle Holder: An Ergonomic Analysis.
As surveys reveal the prevalence of musculoskeletal pain among surgeons, it is important to have an appreciation and understanding of surgical ergonomics to protect against long-term injuries and mitigate the symptoms of existing conditions. Surgeons diagnosed with thumb carpometacarpal (CMC) joint osteoarthritis, a progressive and debilitating condition, can be especially vulnerable to the pain caused by the repetitive manual tasks of operating. In this article, the authors describe a case of occupational thumb CMC arthritis in a right-hand dominant plastic surgeon and provide an ergonomic analysis of the different needle holders. Following diagnosis, the simple switch from the traditional Hegar needle holder to the Mathieu needle driver with its palm grip and rotating ratchet lock mechanism stalled the progression of the disease, allowing the surgeon to continue operating pain free. This is the first report of utilization of an alternative needle holder leading to the resolution of thumb pain. In sharing this case, the authors hope to bring awareness to the importance of hand ergonomics in the operating room and offer a practical tip to surgeons with CMC arthritis.


Phase II study of rabbit anti-thymocyte globulin, cyclosporine and granulocyte colony-stimulating factor in patients with aplastic anemia and myelodysplastic syndrome.
We investigated efficacy and safety of rabbit anti-thymocyte globulin (rATG), cyclosporine and granulocyte colony-stimulating factor (G-CSF) as first-line therapy for patients with aplastic anemia (AA) and low or intermediate-1 or hypoplastic myelodysplastic syndrome (MDS). rATG 3.5 mg/kg (or 2.5 mg/kg per day for patients >or=55 years with MDS) was given for 5 days. Cyclosporine (5 mg/kg) and G-CSF (5 microg/kg) were given daily and continued for up to 6 months or longer. Responses were assessed about 3 and 6 months after therapy. Thirty-six patients have been enrolled on study and 32 patients treated; 25 were evaluable for a response (13 with AA, 12 with MDS); the rest are too early. The median age was 62 years (range, 20-83) for patients with AA and 63 (range, 42-80) for patients with MDS. Of 13 patients, 12 (92%) patients with AA responded (5 complete response (CR), 7 partial response (PR)), whereas of 12 patients, 4 (33%) patients with MDS responded (1 CR, 3 PR). For patients with AA, the median time to response (TTR) was 93 days (range, 79-623), whereas in the MDS group the median TTR was 111 days (range, 77-139). Grade III/IV toxicities were mainly cytopenias and neutropenic fever. Combination of rATG, cyclosporine and G-CSF is safe and effective as first-line treatment of AA and has significant activity in low-risk MDS.


Positivity in healthcare: relation of optimism to performance.
The purpose of this paper is to explore the linkage between nurses' levels of optimism and performance outcomes. The study sample consisted of 78 nurses in all areas of a large healthcare facility (hospital) in the Midwestern United States. The participants completed surveys to determine their current state of optimism. Supervisory performance appraisal data were gathered in order to measure performance outcomes. Spearman correlations and a one-way ANOVA were used to analyze the data. The results indicated a highly significant positive relationship between the nurses' measured state of optimism and their supervisors' ratings of their commitment to the mission of the hospital, a measure of contribution to increasing customer satisfaction, and an overall measure of work performance. This was an exploratory study. Larger sample sizes and longitudinal data would be beneficial because it is probable that state optimism levels will vary and that it might be more accurate to measure state optimism at several points over time in order to better predict performance outcomes. Finally, the study design does not imply causation. Suggestions for effectively developing and managing nurses' optimism to positively impact their performance are provided. To date, there has been very little empirical evidence assessing the impact that positive psychological capacities such as optimism of key healthcare professionals may have on performance. This paper was designed to help begin to fill this void by examining the relationship between nurses' self-reported optimism and their supervisors' evaluations of their performance.


Image texture features predict renal function decline in patients with autosomal dominant polycystic kidney disease.
Magnetic resonance imaging (MRI) examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Height-adjusted TKV (HtTKV) has become the gold-standard imaging biomarker for ADPKD progression at early stages of the disease when estimated glomerular filtration rate (eGFR) is still normal. However, HtTKV does not take advantage of the wealth of information provided by MRI. Here we tested whether image texture features provide additional insights into the ADPKD kidney that may be used as complementary information to existing biomarkers. A retrospective cohort of 122 patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study was identified who had T2-weighted MRIs and eGFR values over 70 mL/min/1.73m2 at the time of their baseline scan. We computed nine distinct image texture features for each patient. The ability of each feature to predict subsequent progression to CKD stage 3A, 3B, and 30% reduction in eGFR at eight-year follow-up was assessed. A multiple linear regression model was developed incorporating age, baseline eGFR, HtTKV, and three image texture features identified by stability feature selection (Entropy, Correlation, and Energy). Including texture in a multiple linear regression model (predicting percent change in eGFR) improved Pearson correlation coefficient from -0.51 (using age, eGFR, and HtTKV) to -0.70 (adding texture). Thus, texture analysis offers an approach to refine ADPKD prognosis and should be further explored for its utility in individualized clinical decision making and outcome prediction.


Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder.
The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.


A method for measuring the energy spectrum of coincidence events in positron emission tomography.
Positron emission tomography (PET) system energy response is typically characterized in singles detection mode, yet there are situations in which the energy spectrum of coincidence events might be different than the spectrum measured in singles mode. Examples include imaging with isotopes that emit a prompt gamma in coincidence with a positron emission, imaging with low activity in a LSO/LYSO-based cameras, in which the intrinsic activity is significant, and in high scatter situations where the two 511 keV photons have different scattering probabilities (i.e. off-center line source). The ability to accurately measure the energy spectrum of coincidence events could be used for validating simulation models, optimizing energy discriminator levels and examining scatter models and corrections. For many PET systems operating in coincidence mode, the only method available for estimating the energy spectrum is to step the lower and upper level discriminators (LLD and ULD). Simple measurement techniques such as using a narrow sliding energy window or stepping only the LLD will not yield a spectrum of coincidence events that is accurate for cases where there are different energy components contributing to the spectrum. In this work we propose a new method of measuring the energy spectrum of coincidence events in PET based on a linear combination of two sets of coincident count measurements: one made by stepping the LLD and one made by stepping the ULD. The method was tested using both Monte Carlo simulations of a Siemens microPET R4 camera and measured data acquired on a Siemens Inveon PET camera. The results show that our energy spectrum calculation method accurately measures the coincident energy spectra for cases including the beta/gamma spectrum of the (176)Lu intrinsic activity present in the LSO scintillator crystals, a (68)Ge source and an (124)I source (in which there are prompt gamma-rays emitted together with the positron).


Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients.
Interferons (IFNs) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, a recent report of ACE2, the host factor mediating SARS-Cov-2 infection, identifying it as interferon-stimulated raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study of 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or computed tomography (CT) scan improvement, whereas late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir alone or together were associated with reduced mortality and accelerated recovery in comparison with treatment with lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 could induce favorable clinical responses.


Consensus document on the prevention of methylmercury exposure in Spain: Study group for the prevention of Me-Hg exposure in Spain (GEPREM-Hg).
The beneficial effects of fish consumption in both children and adults are well known. However, the intake of methylmercury, mainly from contaminated fish and shellfish, can have adverse health effects. The study group on the prevention of exposure to methylmercury (GEPREM-Hg), made up of representatives from different Spanish scientific societies, has prepared a consensus document in a question and answer format, containing the group's main conclusions, recommendations and proposals. The objective of the document is to provide broader knowledge of factors associated with methylmercury exposure, its possible effects on health amongst the Spanish population, methods of analysis, interpretation of the results and economic costs, and to then set recommendations for fish and shellfish consumption. The group sees the merit of all initiatives aimed at reducing or prohibiting the use of mercury as well as the need to be aware of the results of contaminant analyses performed on fish and shellfish marketed in Spain. In addition, the group believes that biomonitoring systems should be set up in order to follow the evolution of methylmercury exposure in children and adults and perform studies designed to learn more about the possible health effects of concentrations found in the Spanish population, taking into account the lifestyle, eating patterns and the Mediterranean diet.


Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.
Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use. To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men. The Physicians' Health Study II, a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14,641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled. Daily multivitamin or placebo. Composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually. During a median follow-up of 11.2 (interquartile range, 10.7-13.3) years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; hazard ratio [HR], 1.01; 95% CI, 0.91-1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; HR, 0.93; 95% CI, 0.80-1.09; P = .39), total stroke (4.1 and 3.9 events per 1000 person-years; HR, 1.06; 95% CI, 0.91-1.23; P = .48), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR, 0.95; 95% CI, 0.83-1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88-1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction). Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up. clinicaltrials.gov Identifier: NCT00270647.


Structure-function analysis of Leishmania lipophosphoglycan. Distinct domains that mediate binding and inhibition of endothelial cell function.
We have shown that Leishmania lipophosphoglycan (LPG) inhibits IL-1 beta gene expression in human monocytes. Here, we show that LPG can bind in a time-dependent manner and suppress endothelial cell activation, possibly via specific LPG domains. Endotoxin (10 ng/ml, 4 h) consistently caused endothelium to increase monocyte adhesion (approximately 20-fold). LPG pretreatment (2 microM, 2 h) completely blocked endotoxin-mediated monocyte adhesion. LPG did not grossly suppress endothelial functions because TNF-alpha- and IL-1 beta-mediated adhesion toward monocytes were not affected. Using four highly purified LPG fragments (namely, repeating phosphodisaccharide (PGM), phosphoglycan, phosphosaccharide core-lyso-alkyl-phosphatidylinositol (core-PI), and lyso-alkyl-phosphatidylinositol (lyso-PI)), we examined whether these fragments can independently inhibit endothelial adhesion. In contrast to that of intact LPG, neither the four LPG fragments (2 microM, 2 h) independently nor the co-addition of phosphoglycan and core-P1 fragments blocked the endotoxin-mediated adhesion to monocytes. To determine whether the fragments can reverse the effect of intact LPG, endothelial cells were first pretreated with the LPG fragments (10 microM, 15 min), followed by the addition of LPG (2 microM). All four LPG fragments fully reversed the effect of LPG. Simultaneous addition of LPG fragments and intact LPG caused only partial suppression (approximately 45%), while the addition of LPG fragments 14 min later had no reversal effect. Flow cytometry revealed that only core-P1 and lyso-P1 competitively inhibited (approximately 30%) LPG binding. Conversely, LPG competed with the binding of [3H]lyso-P1 (approximately 30%). Furthermore, mAb against the PGM reversed (approximately 70%) the effect of LPG. Thus, the lyso-P1 domain on LPG mediates binding to endothelial cells, whereas the PGM domain mediates the cell inhibitory effect.


Role of urinary cathelicidin LL-37 and human β-defensin 1 in uncomplicated Escherichia coli urinary tract infections.
Cathelicidin (LL-37) and human β-defensin 1 (hBD-1) are important components of the innate defense in the urinary tract. The aim of this study was to characterize whether these peptides are important for developing uncomplicated Escherichia coli urinary tract infections (UTIs). This was investigated by comparing urinary peptide levels of UTI patients during and after infection to those of controls, as well as characterizing the fecal flora of participants with respect to susceptibility to LL-37 and in vivo virulence. Forty-seven UTI patients and 50 controls who had never had a UTI were included. Participants were otherwise healthy, premenopausal, adult women. LL-37 MIC levels were compared for fecal E. coli clones from patients and controls and were also compared based on phylotypes (A, B1, B2, and D). In vivo virulence was investigated in the murine UTI model by use of selected fecal isolates from patients and controls. On average, UTI patients had significantly more LL-37 in urine during infection than postinfection, and patient LL-37 levels postinfection were significantly lower than those of controls. hBD-1 showed similar urine levels for UTI patients and controls. Fecal E. coli isolates from controls had higher LL-37 susceptibility than fecal and UTI E. coli isolates from UTI patients. In vivo studies showed a high level of virulence of fecal E. coli isolates from both patients and controls and showed no difference in virulence correlated with the LL-37 MIC level. The results indicate that the concentration of LL-37 in the urinary tract and low susceptibility to LL-37 may increase the likelihood of UTI in a complex interplay between host and pathogen attributes.


Flexible all fiber Fabry-Perot filters based on superimposed chirped fiber Bragg gratings with continuous FSR tunability and its application to a multiwavelength fiber laser.
We proposed and experimentally demonstrate a simple and flexible scheme of all-fiber Fabry-Perot filter with continuous free spectral range tunability exploiting a superimposed chirped fiber Bragg grating. Then, we apply the proposed continuously tunable multichannel filter to a multiwavelength SOA ring laser at room temperature. The specially designed apparatus can induce the symmetrical strain gradient and modify the chirp ratio along the superimposed chirped fiber Bragg grating attached onto a flexible cantilever beam. Then the free spectral range of the all-fiber Fabry-Perot filter can be continuously controlled by the variation of reflection chirp bandwidth of the superimposed chirped fiber Bragg grating without center wavelength shift, which depends on the moving direction of translation stage. The proposed scheme can provide the effective multichannel filter with continuous free spectral range tunability. We successfully achieve the stable operation of a multiwavelength SOA laser with eleven lasing channels based on the proposed flexibly tunable multichannel filter at room temperature.


Quantitative evaluation of equine deep digital flexor tendon morphology using magnetic resonance imaging.
Injury of the distal aspect of the deep digital flexor tendon (DDFT) is a recognized cause of lameness, but diagnosis is difficult. This study aimed to improve understanding of DDFT morphology and pathology using retrospective evaluation of magnetic resonance (MR) images. We hypothesized that: (1) The distal aspect of the DDFT in normal horses would have a repeatable proximal/distal pattern and symmetry between limbs and between lobes; (2) DDFT dimensions would be related to bodyweight, navicular bone dimensions and hoof size; (3) this symmetry and pattern would be lost in DDFT injury; and (4) DDFT size would increase with injury. MR images of 64 live horse limbs, 26 with no identified DDFT lesion and 38 with identified DDFT abnormalities, and 19 normal cadaver limbs were analyzed. Using standardized transverse images, measurements of DDFT cross-sectional area, medial-lateral (ML) width and dorsal-palmar depth were obtained at six preselected sites. A uniform distal to proximal shape pattern was identified in all horses. The flattened crescent shape at the insertion changed to a deeper bilobed shape more proximally, with the mid-navicular area having the greatest cross-sectional area. Strong ML (P < 0.0006) and left/right symmetry (P < 0.02) were observed. In addition, there was a strong association between DDFT cross-sectional area and horse weight (P = 0.005) and between DDFT and navicular bone ML width (P = 0.004). Symmetry between sides or between lobes was lost at sites with a unilateral lesion and correlation between horse weight and DDFT cross-sectional area was lost in the presence of lesions. DDFTs with core lesions had a consistent increase in cross-sectional area overall, but other lesion types had no significant increase in size. The shape and symmetry seen in normal tendons could be related to the mechanical demands placed upon individual lobes. The limited increase in cross-sectional area with injury may be explained by the restrictive structures of the hoof, possibly explaining the ongoing pain seen in such lesions.


[Pulmonary cytotoxicity induced by bleomycin and methotrexate].
Early detection of drug-induced pulmonary parenchymal injuries is often hampered by nonspecific clinical and X-ray manifestations. The diagnosis is usually based on a history of drug use, clinical and X-ray presentation, and exclusion of other causes of lung tissue injury. Chemical preparations most commonly cause pathological pulmonary changes. Overall, about 10% of all patients receiving chemotherapy develop pathological changes in the lung parenchyma. The main chemical preparations causing lung injury are bleomycin, methotrexate, carmustine, busulfan, and cyclophosphamide. Out of all examination techniques, computed tomography is most sensitive in determining the presence, specific features, and trends in the development of drug-induced pulmonary parenchymal disease. The paper gives the data available in the literature and 2 clinical observations of pulmonary parenchymal disease induced by bleomycin and methotrexate.


Continuing professional development evaluation: two rapid review courses in nephrology and rheumatology.
Continuing professional development (CPD) is a novel approach to increase professional knowledge and skills. The aim of this study is to explore participants' characteristics and to understand participants' views on two rapid review courses (RRCs) as part of CPD program, and to assess healthcare providers' views about the use of internet for accessing medical information. Data were collected from 150 participants who attended an RRC in Nephrology and Rheumatology as part of an ongoing CME program. Participants' response rate was 92% and 84.4% in Nephrology and Rheumatology RRCs, respectively. Participants' Mean Age±SD were 39±2.1 and 41±2.1 years in the Nephrology and Rheumatology courses, respectively. Demographic variables, i.e., age, gender, and specialization showed a significant (p<0.01) impact on the learning objectives of the program. Further, participants reported that the course material had a significant (p<0.02) impact on their knowledge. Finding new medical information was the primary motive to search the internet among all participants. About half of the subjects reported knowledge of their preferred medical education sites and had access at their clinical setup. Barriers to internet use included lack of specific information, difficulty to download contents, and excessive material. Professional association websites, online journals, and CME programs were the most frequently searched sources of information. Most of the subjects reported significant (p<0.02) barriers to find medical resources on the internet and to adequately utilize the currently available medical search engines available in the healthcare system. A discipline specific and integrated CPD program may have provided dual benefit such as accredited CME hours and a significant change in the participants' knowledge. There is a need to increase Internet accessibility and capacity in the current healthcare facilities. Future CPD studies should include measuring participants' knowledge and skills "pre and post" course delivery, and a detailed evaluation of the course program.


Stability and Oscillation Analysis of a Gene Regulatory Network With Multiple Time Delays and Diffusion Rate.
In genetic regulatory networks (GRNs), the diffusion rate of mRNA and protein play a key role in regulatory mechanisms of gene expression, especially in translation and transcription. However, the influence of diffusion rate on oscillatory gene expression is not well understood. In this paper, by considering the diffusion rate of mRNA and protein, a novel GRN is proposed. Then, two basic problems of such network, i.e. stability and oscillation, are solved in detail. Moreover, the properties of oscillation are also investigated. it is found that the total biochemistry reaction time can affect the stability of the positive equilibrium and give rise to the oscillation. The diffusion rate of mRNA and proteins have a major impact on the oscillation properties. Finally, two examples not only verify the theoretical results, but also show that a slight diffusion rate increasing may lead to huge change in oscillatory gene expressions.


Determination of the anatomic communications among compartments within the carpus, metacarpophalangeal and metatarsophalangeal joints, stifle joint, and tarsus in llamas.
To determine the anatomic communications among compartments within the carpus, metacarpophalangeal and metatarsophalangeal joints, stifle joint, and tarsus in llamas. 88 limbs from 22 llamas necropsied because of reasons unrelated to disease of the carpus; tarsus; or metacarpophalangeal, metatarsophalangeal, or stifle joints. 1 compartment (randomly assigned) of each joint was injected with blue latex solution. Communication between joint compartments was determined by observation of latex in adjacent compartments following frozen sectioning. Of the 44 carpi, 30 (68%) had anatomic separation between the radiocarpal and middle carpal joints, whereas the remaining 14 (32%) had communication between the radiocarpal and middle carpal joints. In the metacarpophalangeal or metatarsophalangeal joints, medial and lateral joint compartments remained separate in 83 of 88 (94%) joints injected. The tibiotarsal and proximal intertarsal joints communicated in all tarsi examined, whereas 14 of 38 (37%) communicated between the proximal intertarsal and distal intertarsal joints. Communication between the distal intertarsal and tarsometatarsal joints was detected in 17 of 25 (68%) specimens; all 4 tarsal joints communicated in 11 of 42 (26%) specimens examined. Examination of 33 stifle joints that were successfully injected revealed communication between the femoropatellar, medial femorotibial, and lateral femorotibial joints. These data suggest that it is important to determine the joint communications specific to each llama prior to treatment of septic arthritis. The metacarpophalangeal or metatarsophalangeal joint compartments may be considered separate, although the lateral and medial compartments infrequently communicate along the proximal palmar or plantar aspect.


Transformation of the germ line into muscle in mes-1 mutant embryos of C. elegans.
Mutations in the maternal-effect sterile gene mes-1 cause the offspring of homozygous mutant mothers to develop into sterile adults. Lineage analysis revealed that mutant offspring are sterile because they fail to form primordial germ cells during embryogenesis. In wild-type embryos, the primordial germ cell P4 is generated via a series of four unequal stem-cell divisions of the zygote. mes-1 embryos display a premature and progressive loss of polarity in these divisions: P0 and P1 undergo apparently normal unequal divisions and cytoplasmic partitioning, but P2 (in some embryos) and P3 (in most embryos) display defects in cleavage asymmetry and fail to partition lineage-specific components to only one daughter cell. As an apparent consequence of these defects, P4 is transformed into a muscle precursor, like its somatic sister cell D, and generates up to 20 body muscle cells instead of germ cells. Our results show that the wild-type mes-1 gene participates in promoting unequal germ-line divisions and asymmetric partitioning events and thus the determination of cell fate in early C. elegans embryos.


Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.
The oxidative modification of low density lipoprotein (LDL) may play an important role in atherosclerosis. We found that the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) inhibits in vitro LDL oxidation at concentrations much lower than other reported antioxidants. To test whether DPPD could prevent atherosclerosis, New Zealand White rabbits were fed either a diet containing 0.5% cholesterol and 10% corn oil (control group) or the same diet also containing 1% DPPD (DPPD-fed group) for 10 wk. Plasma total cholesterol levels were not different between the two groups, but DPPD feeding increased the levels of triglyceride (73%, P = 0.007) and HDL cholesterol (26%, P = 0.045). Lipoproteins from DPPD-fed rabbits contained DPPD and were much more resistant to oxidation than control lipoproteins. After 10 wk, the DPPD-fed animals had less severe atherosclerosis than did the control animals: thoracic aorta lesion area was decreased by 71% (P = 0.0007), and aortic cholesterol content was decreased by 51% (P = 0.007). Although DPPD cannot be given to humans because it is a mutagen, our results indicate that orally active antioxidants can have antiatherosclerotic activity. This strongly supports the theory that oxidized LDL plays an important role in the pathogenesis of atherosclerosis.


Suicide within 12 months of contact with mental health services: national clinical survey.
To describe the clinical circumstances in which psychiatric patients commit suicide. National clinical survey. England and Wales. A two year sample of people who had committed suicide, in particular those who had been in contact with mental health services in the 12 months before death. Proportion of suicides in people who had had recent contact with mental health services; proportion of suicides in inpatients; proportion of people committing suicide and timing of suicide within three months of hospital discharge; proportion receiving high priority under the care programme approach; proportion who were recently non-compliant and not attending. 10 040 suicides were notified to the study between April 1996 and March 1998, of whom 2370 (24%; 95% confidence interval 23% to 24%) had had contact with mental health services in the year before death. Data were obtained on 2177, a response rate of 92%. In general these subjects had broad social and clinical needs. Alcohol and drug misuse were common. 358 (16%; 15% to 18%) were psychiatric inpatients at the time of death, 21% (17% to 25%) of whom were under special observation. Difficulties in observing patients because of ward design and nursing shortages were both reported in around a quarter of inpatient suicides. 519 (24%; 22% to 26%) suicides occurred within three months of hospital discharge, the highest number occurring in the first week after discharge. 914 (43%; 40% to 44%) were in the highest priority category for community care. 488 (26% excluding people whose compliance was unknown; 24% to 28%) were non-compliant with drug treatment while 486 (28%; 26% to 30%) community patients had lost contact with services. Most people who committed suicide were thought to have been at no or low immediate risk at the final service contact. Mental health teams believed suicide could have been prevented in 423 (22%; 20% to 24%) cases. Several suicide prevention measures in mental health services are implied by these findings, including measures to improve compliance and prevent loss of contact with services. Inpatient facilities should remove structural difficulties in observing patients and fixtures that can be used in hanging. Prevention of suicide after discharge may require earlier follow up in the community. Better suicide prevention in psychiatric patients is likely to need measures to improve the safety of mental health services as a whole, rather than specific measures for people known to be at high risk.


Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrio anguillarum strain 775.
Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site-directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently.


Changes in sequential coronary arteriograms and subsequent coronary events. Surgical Control of the Hyperlipidemias (POSCH) Group.
Assessment of the relationship between changes in sequential coronary arteriograms and subsequent clinical coronary events. The Program on the Surgical Control of the Hyperlipidemias, a randomized secondary atherosclerosis intervention trial, obtained coronary arteriograms at baseline, 3, 5, and 7 or 10 years of follow-up. Assessments of changes between pairs of coronary arteriograms were made by two-member panels blinded to the patients' assigned treatment and to the temporal sequence of the films. The relationship of changes between the baseline and the 3-year follow-up arteriograms and subsequent clinical coronary events was examined. Three university hospitals and one private primary care facility. A total of 838 patients, with 417 patients randomized to the control group and 421 to the intervention group. Of all patients, 695 had baseline and 3-year arteriograms. The control group received American Heart Association Phase II diet instruction and the intervention group received identical dietary instruction plus a partial ileal bypass operation. The use of arteriographic changes as a predictor of subsequent clinical coronary events. Changes between the baseline and the 3-year coronary arteriographic overall disease assessment were significantly associated with subsequent overall and atherosclerotic coronary heart disease mortality (P less than .01). For the combined end point of atherosclerotic coronary heart disease mortality or confirmed nonfatal myocardial infarction, a significant relationship between the overall disease assessment and subsequent clinical events was found in the control group (P less than .0001) and in the surgery group (P = .04). For this combined end point, however, the control and the surgery groups were different with respect to clinical coronary events after 3 years, stratified by the baseline to 3-year overall disease assessment (P less than .001, unadjusted; P = .06, adjusted for 3-year clinical covariates). Coronary arteriographic changes can be used in atherosclerosis intervention trials as a limited surrogate end point for certain clinical coronary events. This relationship is statistically compelling for overall mortality and atherosclerotic coronary heart disease mortality. For an individual patient, changes in the severity of coronary atherosclerosis seen on sequential coronary arteriograms can serve as prognostic indicators for subsequent overall or atherosclerotic coronary heart disease mortality.


Anti-vascular endothelial growth factor for neovascular glaucoma.
Neovascular glaucoma (NVG) is a potentially blinding secondary glaucoma. It is caused by the formation of abnormal new blood vessels which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) agents are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGFs for the control of intraocular pressure (IOP) in NVG. To compare the IOP lowering effects of intraocular anti-VEGF agents to no anti-VEGF treatment, as an adjunct to existing modalities for the treatment of NVG. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 January 2013. We included randomized controlled trials (RCTs) and quasi-RCTs of people treated with anti-VEGF agents for NVG. Two authors independently assessed the search results for trials to be included in the review. Discrepancies were resolved by discussion with a third author. Since no trial met our inclusion criteria, no assessment of risk of bias or meta-analysis was undertaken. No RCTs were found that met the inclusion criteria for this review. Two RCTs of anti-VEGF agents for treating NVG were not included in the review due to the heterogeneity and uncontrolled assignment of adjunct treatments received by the study participants. Currently available evidence is insufficient to evaluate the effectiveness of anti-VEGF treatments, such as intravitreal ranibizumab or bevacizumab, as an adjunct to conventional treatment in lowering IOP in NVG. Well designed RCTs are needed to address this issue, particularly trials that evaluate long-term (at least six months) benefits and risks since the effects of anti-VEGF agents may be short-term only. An RCT comparing anti-VEGF agents with no anti-VEGF agents taking into account the need for co-interventions, such as panretinal photocoagulation (PRP), glaucoma shunt procedures, cyclodestructive procedures, cataract surgery, and deep vitrectomy, could be of use to investigate the additional beneficial effect of anti-VEGF agents in treating NVG. Since decisions for when and which co-interventions should be used are based on clinical criteria, they would not be appropriate for randomization. However, the design of a study on this topic should aim to balance groups by stratification of co-intervention at time of randomization or by enrolling a sufficient number of participants to conduct subgroup analysis by co-interventions (ideally 15 participants per treatment group for each subgroup). Alternatively, the inclusion criteria for a trial could limit participants to those who receive the same co-intervention.


Is pseudo-intractability in population of patients with epilepsy still alive in the 21st century? Audit of 100 seizure-free patients, referred with the diagnosis of pharmacoresistant epilepsy.
There is no universally accepted definition of pseudo-intractable epilepsy. Pseudo-intractability means that the resistance to treatment is, in fact, caused by clinical errors. The purpose of our study was to identify the reasons for intractability and subsequent effective therapeutic management approaches in a group of patients with established pseudo-intractable epilepsy. The study was designed as a retrospective audit of 100 adult patients who, in their past medical history, were diagnosed as having intractable epilepsy but, following adjustments to their medical management, were seizure free for at least 2 years. Patients underwent standard clinical evaluation, including EEG and/or video-EEG monitoring. We re-evaluated past medical, family, seizure and pharmacological history and morphological findings. Epilepsy was re-classified according to the ILAE classification. We identified possible errors including incorrect diagnosis and/or inappropriate previous epilepsy management in all 100 patients. Incorrect diagnosis (seizure type and/or syndrome) was observed in 47 patients (47%). Thirty two patients (32%) with idiopathic generalized epilepsy were treated for complex focal seizures with inappropriate choice of medication. Therapeutic errors were identified in 48 patients (48%). Issues with medication compliance were found in 20 patients (20%). Potential seizure precipitating factors were detected in 23 patients (23%). Our study of 100 patients confirmed that the problem of pseudo-intractability still exists. Every case of pharmacoresistance in epilepsy could potentially be caused by one or more clinical errors.


Intraoperative laparoscope augmentation for port placement and resection planning in minimally invasive liver resection.
In recent years, an increasing number of liver tumor indications were treated by minimally invasive laparoscopic resection. Besides the restricted view, two major intraoperative issues in laparoscopic liver resection are the optimal planning of ports as well as the enhanced visualization of (hidden) vessels, which supply the tumorous liver segment and thus need to be divided (e.g., clipped) prior to the resection. We propose an intuitive and precise method to plan the placement of ports. Preoperatively, self-adhesive fiducials are affixed to the patient's skin and a computed tomography (CT) data set is acquired while contrasting the liver vessels. Immediately prior to the intervention, the laparoscope is moved around these fiducials, which are automatically reconstructed to register the patient to its preoperative imaging data set. This enables the simulation of a camera flight through the patient's interior along the laparoscope's or instruments' axes to easily validate potential ports. Intraoperatively, surgeons need to update their surgical planning based on actual patient data after organ deformations mainly caused by application of carbon dioxide pneumoperitoneum. Therefore, preoperative imaging data can hardly be used. Instead, we propose to use an optically tracked mobile C-arm providing cone-beam CT imaging capability intraoperatively. After patient positioning, port placement, and carbon dioxide insufflation, the liver vessels are contrasted and a 3-D volume is reconstructed during patient exhalation. Without any further need for patient registration, the reconstructed volume can be directly augmented on the live laparoscope video, since prior calibration enables both the volume and the laparoscope to be positioned and oriented in the tracking coordinate frame. The augmentation provides the surgeon with advanced visual aid for the localization of veins, arteries, and bile ducts to be divided or sealed.


Topological Exciton Fermi Surfaces in Two-Component Fractional Quantized Hall Insulators.
A wide variety of two-dimensional electron systems allow for independent control of the total and relative charge density of two-component fractional quantum Hall (FQH) states. In particular, a recent experiment on bilayer graphene (BLG) observed a continuous transition between a compressible and incompressible phase at total filling ν_{T}=1/2 as charge is transferred between the layers, with the remarkable property that the incompressible phase has a finite interlayer polarizability. We argue that this occurs because the topological order of ν_{T}=1/2 systems supports a novel type of interlayer exciton that carries Fermi statistics. If the fermionic excitons are lower in energy than the conventional bosonic excitons (i.e., electron-hole pairs), they can form an emergent neutral Fermi surface, providing a possible explanation of an incompressible yet polarizable state at ν_{T}=1/2. We perform exact diagonalization studies that demonstrate that fermionic excitons are indeed lower in energy than bosonic excitons. This suggests that a "topological exciton metal" hidden inside a FQH insulator may have been realized experimentally in BLG. We discuss several detection schemes by which the topological exciton metal can be experimentally probed.