Multiple Modes of Asexual Reproduction by Tropical and Subtropical Sea Star Larvae: an Unusual Adaptation for Genet Dispersal and Survival.
Sea star larvae (Echinodermata: Asteroidea), collected from the subtropical Northwest Atlantic Ocean, exhibited three distinct modes of asexual reproduction. A number of different bipinnariae and brachiolariae reproduced by paratomous cloning of the posterolateral arms. This morphogenesis was identical to that of larvae assignable to the genus Luidia. A second mode of asexual reproduction involves the autotomization of an anterior portion of the preoral lobe. Primary larvae with preoral lobes of varying sizes and free-swimming preoral lobes of various stages of morphological development were simultaneously collected. The free-swimming preoral lobes developed complete digestive systems and ultimately assumed the form of typical bipinnaria larvae. Asexual reproduction by larvae may also take the form of budding. The released individual is either a blastula- or gastrulastage embryo. Subsequent development to a bipinnariastage secondary larva, with the possible exception of coelom formation, appears to occur through the events associated with normal larval development. These diverse methods of asexual propagation provide a common mechanism to increase the length of larval life and amplify the number of individuals. Thus asexual reproduction by larvae should increase the likelihood of genet representation in the next generation.


The limits of stability in patients with Ménière's disease.
To determine the ability of patients with unilateral Ménière's disease (MD) to reach the corresponding limits of stability and to define the existence of directional constraints. 112 patients with unilateral MD and 30 normal age-matched subjects with no history of equilibrium problems. A computerized dynamic posturography system was used to test the ability of subjects to displace their centre of pressure (COP) to the corresponding limits of stability. The eight targets used were separated by 45 degrees to form a circle around the subject who had to displace their COP to the target. Reaction time, velocity, accuracy and an overall evaluation of the intended movement towards and away from the target were analysed. Other characteristics of the patients were also assessed. A small but significant correlation was found between auditory and vestibular deficit and the different variables studied in the limits of stability test. Three factors were derived from variables obtained with short displacements, and the results are significantly different between patients and controls and are correlated with the period since the last vertigo spell, the level of disability, hearing loss and vestibular deficit. Dynamic balance is moderately impaired in patients with Ménière's disease.


Vaccines and autism: a tale of shifting hypotheses.
Although child vaccination rates remain high, some parental concern persists that vaccines might cause autism. Three specific hypotheses have been proposed: (1) the combination measles-mumps-rubella vaccine causes autism by damaging the intestinal lining, which allows the entrance of encephalopathic proteins; (2) thimerosal, an ethylmercury-containing preservative in some vaccines, is toxic to the central nervous system; and (3) the simultaneous administration of multiple vaccines overwhelms or weakens the immune system. We will discuss the genesis of each of these theories and review the relevant epidemiological evidence.


Reconstituted 3-dimensional human skin as a novel in vitro model for studies of carcinogenesis.
EpiDerm (MatTek Co., MA) is a reconstituted human skin equivalent which exhibits morphological and growth characteristics similar to human skin. This model has previously been utilized to evaluate the cytotoxicity and irritant potential of various cosmetic and household products. In this study, we show for the first time that EpiDerm can be used successfully to evaluate the genotoxicity of different types of known carcinogenic agents such as benzo[a]pyrene (BaP), ultraviolet B radiation (UVB), ultraviolet A radiation (UVA), and psoralen-ultraviolet A radiation (PUVA) at the molecular level. The topical application of 50 microg/cm2 BaP to EpiDerm resulted in the accumulation of BaP-DNA adducts and c-fos and p53 proteins as evidenced by immunohistochemical localization. Similarly, exposure to UVB (50 mJ/cm2) and UVA (2.5 J/cm2) enhanced the epidermal expression of c-fos and p53 proteins in the human skin equivalent. PUVA treatment of EpiDerm, however, resulted in the formation of both DNA-8-MOP adducts and augmented expression of c-fos and p53 proteins. Most of these changes reached a peak 8 h after the treatments except in the case of UVA where maximum changes in the expression of c-fos and p53 proteins were observed 24 h after treatment. These results are similar to those previously reported in human and murine skin following exposure to BaP, UVB, UVA, or PUVA indicating that human skin equivalents can be used as a convenient and cost-effective alternative to animal testing for assessing the genotoxicity and mechanism of action of mutagens/carcinogens in human skin.


[Diagnosis and treatment in acute stroke].
Recently, diagnosis and treatment for transient ischemic attack (TIA) and acute stroke is greatly changing in Japan. Now, TIA is closed up because it has been clarified that TIA attack is very high risk for following stroke. Therefore, TIA patients should be immediately evaluated TIA etiology and be treated after TIA attack as soon as possible in order to prevent following stroke. Medical equipment for stroke such as ultrasound and MRI is improving. In particular, development of MRI study including DWI, T(2)(*), FLAIR, and MRA resulted in accurate diagnosis and etiology of super acute ischemic stroke, and paradoxical embolism, arterial dissection, and aortogenic embolism can be diagnosed in acute stroke patients. t-PA therapy has been approved by Japanese government since 1995, October. t-PA therapy can improve patient outcome due to early recanalization of occluded brain artery. The early recanalization rate was approximately 50% of major artery occlusion. We reported that early recanalization depended on time from stroke onset to IV-t-PA administration. Furthermore, we shown that the large ischemic lesions on diffusion-weighted imaging done before-PA infusion and presence of M1 susceptibility vessel sign were predictor for no-early recanalization and poor outcome. Stroke unit consisting stroke doctors, stroke nurse, and rehabilitation staff can improve patient outcome. In this way, management for acute stroke is greatly changing in Japan.


Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin.
We performed a double-blind, placebo-controlled trial to clinically evaluate the protective and ameliorative effects of ellagic acid-rich pomegranate extract on pigmentation in the skin after ultraviolet ray (UV) irradiation, using female subjects in their 20s to 40s. Thirteen healthy volunteers per group were randomly assigned to three groups; namely, high dose (200 mg/d ellagic acid), low dose (100 mg/d ellagic acid) and control (0 mg/d ellagic acid: placebo). Each group received the respective test foods for 4 wk. Each subject received a 1.5 MED (minimum erythema dose) of UV irradiation on an inside region of the right upper arm, based on the MED value measured on the previous day. Luminance (L), melanin and erythema values were measured before the start of the test food intake, and after 1, 2, 3 and 4 wk following the start of the test food intake. Further, questionnaires were conducted regarding the condition of the skin before the start of the test food intake and at the termination of the test food intake. As a result, decreasing rates of L values from the baseline in the low- and high-dose groups were inhibited by 1.35% and 1.73% respectively, as compared to the control group. Further, a stratified analysis using subjects with a slight sunburn revealed an inhibited decrease of L values compared with the control group at 1, 2 (p<0.01, respectively) and 4 wk (p<0.05) after the start of the test food intake in the low-dose group, and at 2 and 3 wk (p<0.05) in the high-dose group. Furthermore, the results of questionnaires showed ameliorating tendencies due to the test food, in some items such as "brightness of the face" and "stains and freckles." Based on the above-mentioned results, it is suggested that ellagic acid-rich pomegranate extract, ingested orally, has an inhibitory effect on a slight pigmentation in the human skin caused by UV irradiation.


DNA Gold Nanoparticle Motors Demonstrate Processive Motion with Bursts of Speed Up to 50 nm Per Second.
Synthetic motors that consume chemical energy to produce mechanical work offer potential applications in many fields that span from computing to drug delivery and diagnostics. Among the various synthetic motors studied thus far, DNA-based machines offer the greatest programmability and have shown the ability to translocate micrometer-distances in an autonomous manner. DNA motors move by employing a burnt-bridge Brownian ratchet mechanism, where the DNA "legs" hybridize and then destroy complementary nucleic acids immobilized on a surface. We have previously shown that highly multivalent DNA motors that roll offer improved performance compared to bipedal walkers. Here, we use DNA-gold nanoparticle conjugates to investigate and enhance DNA nanomotor performance. Specifically, we tune structural parameters such as DNA leg density, leg span, and nanoparticle anisotropy as well as buffer conditions to enhance motor performance. Both modeling and experiments demonstrate that increasing DNA leg density boosts the speed and processivity of motors, whereas DNA leg span increases processivity and directionality. By taking advantage of label-free imaging of nanomotors, we also uncover Lévy-type motion where motors exhibit bursts of translocation that are punctuated with transient stalling. Dimerized particles also demonstrate more ballistic trajectories confirming a rolling mechanism. Our work shows the fundamental properties that control DNA motor performance and demonstrates optimized motors that can travel multiple micrometers within minutes with speeds of up to 50 nm/s. The performance of these nanoscale motors approaches that of motor proteins that travel at speeds of 100-1000 nm/s, and hence this work can be important in developing protocellular systems as well next generation sensors and diagnostics.


Occurrence of manganese, copper and zinc in myelin. Alterations in the peripheral nervous system of dysmyelinating trembler mutant are at variance with brain mutants (quaking and shiverer).
Mn, Cu and Zn were present in mouse brain at concentrations that were 54, 4 and 14 times higher than in serum. In comparison with control animals, Mn was nearly normal in both quaking and shiverer dysmyelinating mutants. Cu was slightly higher in shiverer; Zn was higher in quaking only when expressed on a dry weight basis. The peripheral nervous system contained lower amounts of Mn, Cu and Zn than brain, (1 6 , 1 8 and 1 2 respectively). All three metals were much higher in trembler (4, 3 and 2-fold increase, respectively). Although higher in shiverer and quaking, Mn did not differ significantly from control. Cu and Zn were similar to control in the sciatic nerve of quaking and shiverer. Brain myelin contained Mn, Cu and Zn concentrations that were slightly smaller than those found in the whole brain. Mn and Cu were higher in the myelin from shiverer by approx. 2- and 3-times, whereas Zn was two-fold reduced. It is speculated that such metals play a role in membrane as cofactors of enzymes, especially those in control of free radical damage, and possibly also in membrane structures as phospholipid counterions.


Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression.
No treatment to date is available which specifically targets bone formation in ankylosing spondylitis (AS). Several recent studies have shown that sclerostin (SOST), a Wnt inhibitor specific to osteocytes and chondrocytes, is down-regulated in AS patients. This suggests Wnt signalling may be upregulated, and application of exogenous recombinant SOST (rSOST) may inhibit Wnt signalling and slow pathological bone formation. The proteoglycan-induced spondylitis (PGISp) mouse model in which we have previously demonstrated downregulated SOST expression, was used for this study. Mice were injected with 2.5 ug rSOST/day for a period of 8 weeks following induction of disease. Axial skeleton disease development was assessed by histology and skeletal changes examined using DEXA. rSOST treatment had no effect on peripheral or axial disease development, bone density or disease severity. Injected rSOST was stable over 8 h and residual levels were evident 24 h after injection, resulting in a cumulative increase in SOST serum levels over the treatment time course. Immunohistochemical examination of SOST levels within the joints in non-rSOST treated PGISp mice showed a significant decrease in the percentage of positive osteocytes in the unaffected joints compared to the affected joints, while no difference was seen in rSOST treated mice. This suggests that rSOST treatment increases the number of SOST-positive osteocytes in unaffected joints but not affected joints, despite having no impact on the number of joints affected by disease. Although not disease-modifying, rSOST treatment did appear to regulate SOST levels in the joints suggesting biological activity. Further dose response studies are required and SOST may require modifications to improve its bone targeting ability in order to affect tissue formation to a meaningful level in this model.


Improvement of speckle statistics in double-wavelength superheterodyne interferometry.
In this paper we analyze the probability density function of the superheterodyne signal obtained in a two-wavelength interferometer from the beat of a local oscillator laser beam with a speckled return beam from a rough target. Theoretical investigation shows that, by using an increased number of spatially separated detectors, one can improve noticeably the detection probability of the superheterodyne signal. Experimental results obtained with a four-quadrant detector are in good agreement with theory.


Measuring the completeness and currency of codified clinical information.
The paper describes how an objective score (CCscore) of the 'completeness' and 'currency' of codified clinical information relevant to the management of diabetes mellitus may be derived for individual practices. A questionnaire was developed and administered to 35 practices and statistical methods were used to test for correlation between the prevalence for diabetes mellitus and the relevant CCscores No significant correlation could be found. The 'quality' of computer-stored information varies widely across English General practices for reasons that are incompletely understood. We demonstrated how CCscores may be calibrated for different 'views' of 'relevance', 'completeness', and 'currency' and yet be consistent across practices for a given 'view'. The potential value of this score and how it may contribute to our understanding of variation in 'information quality' are discussed.


Prevalence and correlates of cytopenias in HIV-infected adults initiating highly active antiretroviral therapy in Uganda.
Cytopenias are the most common HIV-associated hematological abnormality. Cytopenias have been associated with several factors including sex, race/ethnicity, geographical location and comorbidities such as tuberculosis, hepatitis B infection, fever and oral candidiasis. Cytopenias become more prevalent as HIV progresses and are often fatal. Data from resource-limited settings about the prevalence and correlates of cytopenia are limited. Therefore we conducted this cross-sectional study to assess the prevalence and correlates of cytopenia among adult AIDS patients at initiation of HAART in Uganda. 400 HIV-infected subjects who were HAART-naïve or on HAART for ≤ 6 months were enrolled into the Multivitamins, HAART and HIV/AIDS Trial. Anemia was defined according to WHO guidelines as any hemoglobin concentration < 12 g/dl for non-pregnant females and < 13 g/dl for males. Leucopenia and thrombocytopenia were defined using study site laboratory reference ranges for lack of generally accepted definitions for these 2 cell lines as leucopenia if white blood cell count < 2.75 × 109 cells/litre and thrombocytopenia if platelets < 125 × 109 cells/litre for females and < 156 × 109 cells/litre for males. Univariate and bivariate analyses were done to describe the patient population and log-binomial regression was used to quantify the correlates of cytopenia. Sixty five percent of the 400 subjects had at least one form of cytopenia. Anemia occurred in 47.8%, leucopenia in 24.3%, thrombocytopenia in 8.3%, bicytopenia in 21.9% and only 2 had a pancytopenia. Cytopenia was more prevalent in females (prevalence ratio [PR]:1.33, 95% confidence interval [CI]:1.12-1.59); CD4 count category 50 to <200 (PR: 0.75, 95% CI: 0.64 -0.88) and CD4 count category 200 to <350 (PR: 0.74, 95% CI: 0.59 - 0.92) compared to CD4 count category <50; normal BMI (PR: 0.82, 95% CI:0.68-1.00) and overweight BMI (PR: 0.64, 95% CI:0.50- 0.82) compared to underweight BMI and those with a history or presence of oral candidiasis. Cytopenias are a frequent complication in HIV-infected adults at initiation of HAART in Uganda. The presence of any cytopenia was associated with female sex, decreasing CD4 count and decreasing body mass index. Prospective studies in resource-limited settings on the trend in HIV-related cytopenias are needed.


The association between interleukin-6 polymorphisms and systemic lupus erythematosus: a meta-analysis.
The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between the IL-6 polymorphisms and SLE using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) the additive model. A total of 11 studies were considered in this study, and ethnicity-specific meta-analysis was performed on European and Asian populations. Meta-analysis of the IL-6 -174 G/C polymorphism showed an association between SLE and the IL-6 -174 G allele in all study subjects (odds ratio (OR) = 1.344, 95% confidence interval (CI) = 1.052-1.718, p = 0.018). Furthermore, stratification by ethnicity indicated an association between the IL-6 -174 G allele and SLE in Europeans (OR = 1.264, 95% CI = 1.037-1.541, p = 0.020). Meta-analysis of the IL-6 -572 G/C polymorphism revealed that an association was found between SLE and the IL-6 -572 G/C polymorphism using the recessive model, but ethnicity-specific meta-analysis revealed no association between SLE and the IL-6 -572 G/C polymorphism in Asians. In conclusion, this meta-analysis demonstrates that the IL-6 -174 G/C polymorphism may confer susceptibility to SLE in Europeans, but that the IL-6 -572 G/C polymorphism is not associated with susceptibility to SLE in Asians.


Effects-Driven Participatory Design: Learning from Sampling Interruptions.
Participatory design (PD) can play an important role in obtaining benefits from healthcare information technologies, but we contend that to fulfil this role PD must incorporate feedback from real use of the technologies. In this paper we describe an effects-driven PD approach that revolves around a sustained focus on pursued effects and uses the experience sampling method (ESM) to collect real-use feedback. To illustrate the use of the method we analyze a case that involves the organizational implementation of electronic whiteboards at a Danish hospital to support the clinicians' intra- and interdepartmental coordination. The hospital aimed to reduce the number of phone calls involved in coordinating work because many phone calls were seen as unnecessary interruptions. To learn about the interruptions we introduced an app for capturing quantitative data and qualitative feedback about the phone calls. The investigation showed that the electronic whiteboards had little potential for reducing the number of phone calls at the operating ward. The combination of quantitative data and qualitative feedback worked both as a basis for aligning assumptions to data and showed ESM as an instrument for triggering in-situ reflection. The participant-driven design and redesign of the way data were captured by means of ESM is a central contribution to the understanding of how to conduct effects-driven PD.


Weighing patients within cognitive-behavioural therapy for eating disorders: How, when and why.
While weight, beliefs about weight and weight changes are key issues in the pathology and treatment of eating disorders, there is substantial variation in whether and how psychological therapists weigh their patients. This review considers the reasons for that variability, highlighting the differences that exist in clinical protocols between therapies, as well as levels of reluctance on the part of some therapists and patients. It is noted that there have been substantial changes over time in the recommendations made within therapies, including cognitive-behavioural therapy (CBT). The review then makes the case for all CBT therapists needing to weigh their patients in session and for the patient to be aware of their weight, in order to give the best chance of cognitive, emotional and behavioural progress. Specific guidance is given as to how to weigh, stressing the importance of preparation of the patient and presentation, timing and execution of the task. Consideration is given to reasons that clinicians commonly report for not weighing patients routinely, and counter-arguments and solutions are presented. Finally, there is consideration of procedures to follow with some special groups of patients.


Cardiac xenotransplantation.
The severe shortage of human donor hearts has prompted several investigators to develop alternative strategies using cross-specie organs or xenografts. Unlike human allotransplantation, in which the important antigenic differences between donor and recipient are confined to the major histocompatibility and blood group antigens, xenotransplantation is confronted with the potential for multiple antigenic differences. In the pig-to-primate model of xenotransplantation, the primary obstacle to cross-species transplantation has been hyperacute rejection mediated by complement fixing antibodies directed against galactose alpha 1,3-galactose (Gal alpha 1,3-Gal) epitopes on the pig endothelium. Conventional immunosuppression is unable to overcome hyperacute rejection; however, recent efforts in molecular biology have focused on genetically engineering porcine donors to express human proteins in their tissue. Transgenic pigs that express human complement regulatory proteins on their endothelium have been developed. Heterotopic transplantation of these transgenic donor hearts have had only moderate success. Alternative approaches attempt to eliminate the Gal alpha 1,3-Gal epitopes by genetically "knocking out" the enzyme necessary for its synthesis, or to reduce the expression of Gal alpha 1,3-Gal epitopes by genetically inserting enzymes that redirect precursor molecules into alternative synthetic pathways. The technology to knock out the necessary enzymes in pigs is not yet available; however, pigs expressing the H-transferase gene have been developed and show reduced levels of Gal alpha 1,3-Gal epitopes. Although this "new breed" of transgenic pigs may overcome the barrier of hyperacute rejection, special strategies will need to be developed that target the next barrier of xenograft rejection.


Nuclear and mitochondrial DNA sequences from two Denisovan individuals.
Denisovans, a sister group of Neandertals, have been described on the basis of a nuclear genome sequence from a finger phalanx (Denisova 3) found in Denisova Cave in the Altai Mountains. The only other Denisovan specimen described to date is a molar (Denisova 4) found at the same site. This tooth carries a mtDNA sequence similar to that of Denisova 3. Here we present nuclear DNA sequences from Denisova 4 and a morphological description, as well as mitochondrial and nuclear DNA sequence data, from another molar (Denisova 8) found in Denisova Cave in 2010. This new molar is similar to Denisova 4 in being very large and lacking traits typical of Neandertals and modern humans. Nuclear DNA sequences from the two molars form a clade with Denisova 3. The mtDNA of Denisova 8 is more diverged and has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over an extended period. The nuclear DNA sequence diversity among the three Denisovans is comparable to that among six Neandertals, but lower than that among present-day humans.


Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes.
Site-specific deletions in the tal-1 gene are reported to occur in 12-26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T-ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T-ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR-delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions.


Estimation of daily energy expenditure in pregnant and non-pregnant women using a wrist-worn tri-axial accelerometer.
Few studies have compared the validity of objective measures of physical activity energy expenditure (PAEE) in pregnant and non-pregnant women. PAEE is commonly estimated with accelerometers attached to the hip or waist, but little is known about the validity and participant acceptability of wrist attachment. The objectives of the current study were to assess the validity of a simple summary measure derived from a wrist-worn accelerometer (GENEA, Unilever Discover, UK) to estimate PAEE in pregnant and non-pregnant women, and to evaluate participant acceptability. Non-pregnant (N = 73) and pregnant (N = 35) Swedish women (aged 20-35 yrs) wore the accelerometer on their wrist for 10 days during which total energy expenditure (TEE) was assessed using doubly-labelled water. PAEE was calculated as 0.9×TEE-REE. British participants (N = 99; aged 22-65 yrs) wore accelerometers on their non-dominant wrist and hip for seven days and were asked to score the acceptability of monitor placement (scored 1 [least] through 10 [most] acceptable). There was no significant correlation between body weight and PAEE. In non-pregnant women, acceleration explained 24% of the variation in PAEE, which decreased to 19% in leave-one-out cross-validation. In pregnant women, acceleration explained 11% of the variation in PAEE, which was not significant in leave-one-out cross-validation. Median (IQR) acceptability of wrist and hip placement was 9(8-10) and 9(7-10), respectively; there was a within-individual difference of 0.47 (p<.001). A simple summary measure derived from a wrist-worn tri-axial accelerometer adds significantly to the prediction of energy expenditure in non-pregnant women and is scored acceptable by participants.


Negative Control Outcomes and the Analysis of Standardized Mortality Ratios.
In occupational cohort mortality studies, epidemiologists often compare the observed number of deaths in the cohort to the expected number obtained by multiplying person-time accrued in the study cohort by the mortality rate in an external reference population. Interpretation of the result may be difficult due to noncomparability of the occupational cohort and reference population with respect to unmeasured risk factors for the outcome of interest. We describe an approach to estimate an adjusted standardized mortality ratio (aSMR) to control for such bias. The approach draws on methods developed for the use of negative control outcomes. Conditions necessary for unbiased estimation are described, as well as looser conditions necessary for bias reduction. The approach is illustrated using data on bladder cancer mortality among male Oak Ridge National Laboratory workers. The SMR for bladder cancer was elevated among hourly-paid males (SMR = 1.9; 95% confidence interval [CI] = 1.3, 2.7) but not among monthly-paid males (SMR = 1.0; 95% CI = 0.67, 1.3). After indirect adjustment using the proposed approach, the mortality ratios were similar in magnitude among hourly- and monthly-paid men (aSMR = 2.2; 95% CI = 1.5, 3.2; and, aSMR = 2.0; 95% CI = 1.4, 2.8, respectively). The proposed adjusted SMR offers a complement to typical SMR analyses.


JIB-04 Has Broad-Spectrum Antiviral Activity and Inhibits SARS-CoV-2 Replication and Coronavirus Pathogenesis.
Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with a 50% effective concentration of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed in vitro antiviral activity in multiple cell types, including primary human bronchial epithelial cells, against several DNA and RNA viruses, including porcine coronavirus transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved weight gain and survival. These results highlight the potential utility of JIB-04 as an antiviral agent against SARS-CoV-2 and other viral pathogens. IMPORTANCE The coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2 infection, is an ongoing public health disaster worldwide. Although several vaccines are available as a preventive measure and the FDA approval of an orally bioavailable drug is on the horizon, there remains a need for developing antivirals against SARS-CoV-2 that could work on the early course of infection. By using infectious reporter viruses, we screened small-molecule inhibitors for antiviral activity against SARS-CoV-2. Among the top hits was JIB-04, a compound previously studied for its anticancer activity. Here, we showed that JIB-04 inhibits the replication of SARS-CoV-2 as well as different DNA and RNA viruses. Furthermore, JIB-04 conferred protection in a porcine model of coronavirus infection, although to a lesser extent when given as therapeutic rather than prophylactic doses. Our findings indicate a limited but still promising utility of JIB-04 as an antiviral agent in the combat against COVID-19 and potentially other viral diseases.


Estimating and mitigating the risk of COVID-19 epidemic rebound associated with reopening of international borders in Vietnam: a modelling study.
Vietnam has emerged as one of the world's leading success stories in responding to COVID-19. After a prolonged period of little to no transmission, there was an outbreak of unknown source in July, 2020, in the Da Nang region, but the outbreak was quickly suppressed. We aimed to use epidemiological, behavioural, demographic, and policy data from the COVID-19 outbreak in Da Nang to calibrate an agent-based model of COVID-19 transmission for Vietnam, and to estimate the risk of future outbreaks associated with reopening of international borders in the country. For this modelling study, we used comprehensive data from June 15 to Oct 15, 2020, on testing, COVID-19 cases, and quarantine breaches within an agent-based model of SARS-CoV-2 transmission to model a COVID-19 outbreak in Da Nang in July, 2020. We applied this model to quantify the risk of future outbreaks in Vietnam in the 3 months after the reopening of international borders, under different behavioural scenarios, policy responses (ie, closure of workplaces and schools), and ongoing testing. We estimated that the outbreak in Da Nang between July and August, 2020, resulted in substantial community transmission, and that higher levels of symptomatic testing could have mitigated this transmission. We estimated that the outbreak peaked on Aug 2, 2020, with an estimated 1060 active infections (95% projection interval 890-1280). If the population of Vietnam remains highly compliant with mask-wearing policies, our projections indicate that the epidemic would remain under control even if a small but steady flow of imported infections escaped quarantine into the community. However, if complacency increases and testing rates are relatively low (10% of symptomatic individuals are tested), the epidemic could rebound again, resulting in an estimated 2100 infections (95% projected interval 1050-3610) in 3 months. These outcomes could be mitigated if the behaviour of the general population responds dynamically to increases in locally acquired cases that exceed specific thresholds, but only if testing of symptomatic individuals is also increased. The successful response to COVID-19 in Vietnam could be improved even further with higher levels of symptomatic testing. If the previous approaches are used in response to new COVID-19 outbreaks, epidemic control is possible even in the presence of low levels of imported cases. Ministry of Science and Technology (Vietnam). For the Vietnamese translation of the abstract see Supplementary Materials section.


Investigation of range profiles from buried 3-D object based on the EM simulation.
The 1-D range profiles are suitable features for target identification and target discrimination because they provide discriminative information on the geometry of the target. To resolve features of the buried target, the contribution from individual scattering centers of the buried target in the range profiles need to be identified. Thus, the study of complex scattering mechanisms from which the range profiles are produced is of great importance. In order to clearly establish the relationship between the range profile characteristics and the complicated electromagnetic (EM) scattering mechanisms, such as reflections and diffractions, a buried cuboid possessing straight edges is chosen as the buried target in this paper. By performing an inverse discrete Fourier transform (IDFT) on the wideband backscattered field data computed with an accurate and fast EM method, the 1-D range profiles of the buried cuboid is successfully simulated. The simulated range profiles provide information about the position and scattering strength of the cuboid's scattering centers along the range direction. Meanwhile, a predicted distribution of the scattering centers is quantitatively calculated for the buried cuboid based on the ray path computation. Good agreement has been found between simulated and predicted locations of the range profiles. Validation for amplitudes of the range profiles is further provided in the research. Both the peak amplitudes and locations of the range profiles could be understood and analyzed based on the knowledge of the scattering mechanisms. The formation of the 1-D range profiles has been revealed clearly from the full analysis of the scattering mechanisms and contributions. The problem has been solved for both near and far field regions. Finally, the buried depth and the characteristic size of the object are reasonably deduced from the simulated range profiles.


In-vivo validation of interpolation-based phase offset correction in cardiovascular magnetic resonance flow quantification: a multi-vendor, multi-center study.
A velocity offset error in phase contrast cardiovascular magnetic resonance (CMR) imaging is a known problem in clinical assessment of flow volumes in vessels around the heart. Earlier studies have shown that this offset error is clinically relevant over different systems, and cannot be removed by protocol optimization. Correction methods using phantom measurements are time consuming, and assume reproducibility of the offsets which is not the case for all systems. An alternative previously published solution is to correct the in-vivo data in post-processing, interpolating the velocity offset from stationary tissue within the field-of-view. This study aims to validate this interpolation-based offset correction in-vivo in a multi-vendor, multi-center setup. Data from six 1.5 T CMR systems were evaluated, with two systems from each of the three main vendors. At each system aortic and main pulmonary artery 2D flow studies were acquired during routine clinical or research examinations, with an additional phantom measurement using identical acquisition parameters. To verify the phantom acquisition, a region-of-interest (ROI) at stationary tissue in the thorax wall was placed and compared between in-vivo and phantom measurements. Interpolation-based offset correction was performed on the in-vivo data, after manually excluding regions of spatial wraparound. Correction performance of different spatial orders of interpolation planes was evaluated. A total of 126 flow measurements in 82 subjects were included. At the thorax wall the agreement between in-vivo and phantom was - 0.2 ± 0.6 cm/s. Twenty-eight studies were excluded because of a difference at the thorax wall exceeding 0.6 cm/s from the phantom scan, leaving 98. Before correction, the offset at the vessel as assessed in the phantom was - 0.4 ± 1.5 cm/s, which resulted in a - 5 ± 16% error in cardiac output. The optimal order of the interpolation correction plane was 1st order, except for one system at which a 2nd order plane was required. Application of the interpolation-based correction revealed a remaining offset velocity of 0.1 ± 0.5 cm/s and 0 ± 5% error in cardiac output. This study shows that interpolation-based offset correction reduces the offset with comparable efficacy as phantom measurement phase offset correction, without the time penalty imposed by phantom scans. The study was registered in The Netherlands National Trial Register (NTR) under TC 4865 . Registered 19 September 2014. Retrospectively registered.


Raman spectroscopy detects and distinguishes neuroblastoma and related tissues in fresh and (banked) frozen specimens.
Raman spectroscopy has been shown to accurately distinguish different neural crest-derived pediatric tumors. This study tests the ability of Raman spectroscopy to accurately identify cryopreserved tissue specimens using a classification algorithm designed from fresh tumor data and vice versa. Fresh specimens of neuroblastoma and other pediatric neural crest tumors were analyzed with Raman spectroscopy. After analysis, the specimens were stored at -80 degrees C. At a later date, the specimens were thawed and reanalyzed by Raman spectroscopy. A computer algorithm was used to classify the spectra from the frozen tissue against a computer model built on the fresh tissue data. This classification process was then reversed, testing fresh spectra against a model built from frozen data. We collected 1114 spectra (862 fresh and 252 frozen) from 62 tissue samples, including 8 normal adrenal glands, 29 neuroblastomas, 14 ganglioneuromas, 8 nerve sheath tumors, and 3 pheochromocytomas. At the tissue level, frozen neuroblastoma, ganglioneuroma, nerve sheath tumor, and pheochromocytoma were distinguished from normal adrenal tissue with 100% sensitivity and specificity. Fresh tissue had the same results except for the misclassification of one specimen of nerve sheath tumor. The representative spectra show a high correlation between fresh and frozen tissue, and a clear difference between pathologic conditions. Spectra from frozen tissue can be accurately classified against spectra from fresh tissue and vice versa. This modality makes it possible to determine in a few minutes a result that often takes 12 to 36 hours for tissue processing and consideration by a trained pathologist to achieve.


Polysaccharopeptide from Coriolus versicolor has potential for use against human immunodeficiency virus type 1 infection.
Polysaccharopeptide (PSP) isolated from the edible mushroom Coriolus versicolor was tested for its potential as an anti-human immunodeficiency virus type 1 (HIV-1) compound in a series of in vitro assays. It demonstrated inhibition of the interaction between HIV-1 gp 120 and immobilized CD4 receptor (IC50 = 150 microg/ml), potent inhibition of recombinant HIV-1 reverse transcriptase (IC50 = 6.25 microg/ml), and inhibited a glycohydrolase enzyme associated with viral glycosylation. These properties, coupled with its high solubility in water, heat-stability and low cytotoxicity, make it a useful compound for further studies on its possible use as an anti-viral agent in vivo.


Neonatal adiposity increases the risk of atopic dermatitis during the first year of life.
Early nutrition and adiposity have been linked to atopic dermatitis (AD) development. We sought to describe risk factors for AD in the first year of life in infants participating in the Cork BASELINE birth cohort study (n = 1537). Prospective data on early-life events, infant feeding, and nutritional and environmental exposures were collected at 15 weeks' gestation, birth, and 2, 6, and 12 months of age. Body composition was assessed by using air displacement plethysmography at day 2 and 2 months. The primary outcome, persistent AD, was determined if the U.K. Working Party Diagnostic Criteria were satisfied at both 6 and 12 months. At 6 and 12 months, the point prevalence of AD was 14.2% (99% CI, 10.5% to 17.8%) and 13.7% (99% CI, 10.3% to 17.6%), respectively; 7.5% (99% CI, 5.0% to 9.9%) of infants had AD at both 6 and 12 months of age. At hospital discharge, 35% of infants were exclusively breast-fed, decreasing to 14% by 2 months. Complementary feeding was commenced at a median of 19 weeks (interquartile range, 17-22 weeks; 19% at <17 weeks and 6% at ≥26 weeks). Median fat mass at day 2 was 0.35 kg (interquartile range, 0.25-0.48 kg). A parental history of atopic disease was self-reported by 43% of mothers and 34% of fathers. Risk factors for AD at 6 and 12 months were maternal atopy (adjusted odds ratio, 2.99; 99% CI, 1.35-6.59; P = .0004) and fat mass of the 80th percentile or greater at day 2 (adjusted odds ratio, 2.31; 99% CI, 1.02-2.25; P = .009). This is the first report of neonatal adiposity as a predictor of AD at 6 and 12 months of age in a well-characterized atopic disease-specific birth cohort.


Evaluation of computational docking to identify pregnane X receptor agonists in the ToxCast database.
The pregnane X receptor (PXR) is a key transcriptional regulator of many genes [e.g., cytochrome P450s (CYP2C9, CYP3A4, CYP2B6), MDR1] involved in xenobiotic metabolism and excretion. As part of an evaluation of different approaches to predict compound affinity for nuclear hormone receptors, we used the molecular docking program GOLD and a hybrid scoring scheme based on similarity weighted GoldScores to predict potential PXR agonists in the ToxCast database of pesticides and other industrial chemicals. We present some of the limitations of different in vitro systems, as well as docking and ligand-based computational models. Each ToxCast compound was docked into the five published crystallographic structures of human PXR (hPXR), and 15 compounds were selected based on their consensus docking scores for testing. In addition, we used a Bayesian model to classify the ToxCast compounds into PXR agonists and nonagonists. hPXR activation was determined by luciferase-based reporter assays in the HepG2 and DPX-2 human liver cell lines. We tested 11 compounds, of which 6 were strong agonists and 2 had weak agonist activity. Docking results of additional compounds were compared with data reported in the literature. The prediction sensitivity of PXR agonists in our sample ToxCast data set (n = 28) using docking and the GoldScore was higher than with the hybrid score at 66.7%. The prediction sensitivity for PXR agonists using GoldScore for the entire ToxCast data set (n = 308) compared with data from the NIH (National Institutes of Health) Chemical Genomics Center data was 73.8%. Docking and the GoldScore may be useful for prioritizing large data sets prior to in vitro testing with good sensitivity across the sample and entire ToxCast data set for hPXR agonists.


Global climate adaptation governance: Why is it not legally binding?
In the last decade, the United Nations Framework Convention on Climate Change has moved from a strong focus on mitigation to increasingly address adaptation. Climate change is no longer simply about reducing emissions, but also about enabling countries to deal with its impacts. Yet, most studies of the climate regime have focused on the evolution of mitigation governance and overlooked the increasing number of adaptation-related decisions and initiatives. In this article, we identify the body of rules and commitments on adaptation and suggest that there are more attempts to govern adaptation than many mitigation-focused accounts of the international climate regime would suggest. We then ask: to what degree are adaptation rules and commitments legalized in the United Nations Framework Convention on Climate Change? We examine the degree of precision and obligation of relevant decisions through an extensive analysis of primary United Nations Framework Convention on Climate Change documents, secondary literature on adaptation initiatives and institutions, interviews with climate change experts and negotiators, and participant observation at climate negotiations. Our analysis finds that adaptation governance is low in precision and obligation. We suggest that this is partly because adaptation is a contested global public good and because 'package deals' are made with mitigation commitments. This article makes a vital contribution to the global environmental politics literature given that adaptation governance is under-studied and poorly understood. It also contributes to the legalization literature by highlighting how contested global public goods may be governed globally, but with low obligation and precision.


Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury.
We determined that renal proximal tubular (PT) NF-κB essential modulator (NEMO) plays a direct and critical role in ischemic acute kidney injury (AKI) using mice lacking renal PT NEMO and by targeted renal PT NEMO inhibition with mesoscale nanoparticle-encapsulated NEMO binding peptide (NBP MNP). We subjected renal PT NEMO-deficient mice, WT mice, and C57BL/6 mice to sham surgery or 30 minutes of renal ischemia and reperfusion (IR). C57BL/6 mice received NBP MNP or empty MNP before renal IR injury. Mice treated with NBP MNP and mice deficient in renal PT NEMO were protected against ischemic AKI, having decreased renal tubular necrosis, inflammation, and apoptosis compared with control MNP-treated or WT mice, respectively. Recombinant peptidylarginine deiminase type 4 (rPAD4) targeted kidney PT NEMO to exacerbate ischemic AKI in that exogenous rPAD4 exacerbated renal IR injury in WT mice but not in renal PT NEMO-deficient mice. Furthermore, rPAD4 upregulated proinflammatory cytokine mRNA and NF-κB activation in freshly isolated renal proximal tubules from WT mice but not from PT NEMO-deficient mice. Taken together, our studies suggest that renal PT NEMO plays a critical role in ischemic AKI by promoting renal tubular inflammation, apoptosis, and necrosis.


Typical household vacuum cleaners: the collection efficiency and emissions characteristics for fine particles.
The issue of fine particle (PM2.5) exposures and their potential health effects is a focus of scientific research because of the recently promulgated National Ambient Air Quality Standard for PM2.5. Before final implementation, the health and exposure basis for the standard will be reviewed by the U.S. Environmental Protection Agency within the next five years. As part of this process, it is necessary to understand total particle exposure issues and to determine the relative importance of the origin of PM2.5 exposure in various micro-environments. The results presented in this study examine emissions of fine particles from a previously uncharacterized indoor source: the residential vacuum cleaner. Eleven standard vacuum cleaners were tested for the emission rate of fine particles by their individual motors and for their efficiency in collecting laboratory-generated fine particles. An aerosol generator was used to introduce fine potassium chloride (KCl) particles into the vacuum cleaner inlet for the collection efficiency tests. Measurements of the motor emissions, which include carbon, and the KCl aerosol were made using a continuous HIAC/Royco 5130 A light-scattering particle detector. All tests were conducted in a metal chamber specifically designed to completely contain the vacuum cleaner and operate it in a stationary position. For the tested vacuum cleaners, fine particle motor emissions ranged from 9.6 x 10(4) to 3.34 x 10(8) particles/min, which were estimated to be 0.028 to 176 micrograms/min for mass emissions, respectively. The vast majority of particles released were in the range of 0.3-0.5 micron in diameter. The lowest particle emission rate was obtained for a vacuum cleaner that had a high efficiency (HEPA) filter placed after the vacuum cleaner bag and the motor within a sealed exhaust system. This vacuum cleaner removed the KCl particles that escaped the vacuum cleaner bag and the particles emitted by the motor. Results obtained for the KCl collection efficiency tests show > 99% of the fine particles were captured by the two vacuum cleaners that used a HEPA filter. A series of tests conducted on two vacuum cleaners found that the motors also emitted ultra-fine particles above 0.01 micron in diameter at rates of greater than 10(8) ultra-fine particles/CF of air. The model that had the best collection efficiency for fine particles also reduced the ultra-fine particle emissions by a factor of 1 x 10(3).


Predictive and prognostic impact of tumour-infiltrating lymphocytes in triple-negative breast cancer treated with neoadjuvant chemotherapy.
In locally and locally advanced triple-negative breast cancer (TNBC), neoadjuvant chemotherapy (NAC) only induces a pCR in 30-35% of patients. Clinical and pathological factors are not enough to distinguish the patients who have no chance of a pCR or not. The tumour microenvironment is critical for cancer and tumour-infiltrating lymphocytes (TIL). Moreover, the NAC scenario is the perfect setting to study possible changes in TIL levels. Using our prospective maintained breast cancer (BC) database, we identified 164 TNBC patients treated with NAC between 1998 and 2015 with enough samples of diagnostic biopsy and after surgery. Evaluation of TILs before and after NAC followed a standardised methodology for visual assessment on haematoxylin-eosin sections and the amounts of TILs were quantitated in deciles. We categorised lymphocyte-predominant breast cancer cutoff according to a receiver operating characteristic (ROC) analysis. We categorised LPBC as involving > 40% lymphocytic infiltration tumour stroma. The primary end point was predictive value of TILs to NAC, and the secondary end point was disease-free survival (DFS). DFS was analysed using the Kaplan-Meier method and the groups were compared with a long-rank test. Univariate and multivariate Cox models were used to generate hazard ratios for determining associations between variables such as TIL after NAC and DFS. A total of 164 TNBC patients were treated with NAC and surgery. The main patients' characteristics are listed in Table 1. We identify different pathological complete response to anthracycline and taxane-based NAC; LPBC subgroup 51 from 58 patients (88%) pCR versus non- lymphocyte-predominant breast cancer (LPBC) subgroup 10 from 106 (9%) pCR, p = 0.001. At a median follow-up of 78 months, LPBC was associated with better DFS; the three-year Kaplan-Meier estimates for DFS were 2% and 30 % for patients with LPBC and non-LPBC, respectively, p = 0.01. Univariate and multivariate analysis confirmed TIL to be an independent prognostic marker of DFS. Tumour-infiltrating lymphocytes could be routinely used in locally advanced TNBC treated with anthracycline and taxane, such as biomarker, to be enabled the identification of different two subgroups: LPBC patients have a very high response to NAC pCR 88%, meanwhile non-LPBC patients only achieve 9%. Moreover, non-LPBC patients have a worse prognosis than LPBC patients. This data verified the predictive and prognostic value of TIL.


Quantification of a mercapturate metabolite of the biocides methylisothiazolinone and chloromethylisothiazolinone ("M-12") in human urine using online-SPE-LC/MS/MS.
Methylisothiazolinone and the reaction mixture of chloromethylisothiazolinone/methylisothiazolinone (MCI/MI, 3 : 1) are broadly used biocides that are contained in many products of everyday life (e.g. cosmetics, wet wipes, etc.). As MI and MCI are able to sensitize (and penetrate) the skin, their application in cosmetic products is of concern. In previous work, we have revealed a background exposure of the general population to MI and/or MCI/MI (3 : 1) by the determination of urinary N-methylmalonamic acid (NMMA) as the main human metabolite. To corroborate these findings, we have now developed a two-dimensional LC/MS/MS method for the quantification of a mercapturic acid metabolite of MI and MCI ((acetylamino){[3-(methylamino)-1-(methylthio)-3-oxopropyl]thio}acetic acid or shortly "M-12") in human urine. This analyte is enriched online using a Strata-X-column and stripped from the urinary matrix. Then, the analyte is back flushed to the analytical column (Phenomenex C18(2), 150 × 4.6 mm) and finally quantified by tandem mass spectrometry with the use of isotopically labelled M-12 as the internal standard. The LOQ for M-12 was 0.2 ng mL-1 urine and sufficient to quantify urinary background levels. Precision within and between series for M-12 in urine at concentrations varying from 0.2 to 5 ng mL-1 ranged from 2.1 to 23.9% and accuracy ranged from 86.3 to 101.8%. Mean accuracy for M-12 in individual urine samples was 94.3% (range: 89.7-102.9%). We applied this method to previously collected 24 h urine samples of 60 persons with no specific exposure to MI and/or MCI/MI (3 : 1). The metabolite M-12 could be quantified in each urine sample. The median and 95th percentile levels for urinary M-12 were determined to be 0.62 and 2.26 ng mL-1, respectively. In these urine samples, the concentrations of the previously determined metabolite NMMA and M-12 correlated well. In the future, we will apply this method to urine samples of a previously conducted human exposure study to explore the additional value of M-12 as a biomarker of exposure to MI and MCI.


Reliability, Stability and Validity of the Brazilian Adaptation of the Oliveira Questionnaire on Low Back Pain in Young People.
The objective of this study was to adapt the Brazilian version, and verify the validity, reliability and internal consistency of the Oliveira questionnaire on low back pain in young people. The questionnaire was translated from European Portuguese into Brazilian Portuguese by means of translation and re-translation. The validity of the contents was determined by experts who analyzed the clarity and pertinence of the questions. Fifteen young people aged 15 to 18 took part in the pre-test step (qualitative analysis), 40 in the test-retest (reliability) and 679 in the evaluation of internal consistency. The intra-class correlation coefficient and Spearman's correlation coefficient were used in the reliability analysis (test-retest), and Cronbach's alpha to determine the internal consistency (stability). In the translation phase the questionnaire was modified and considered suitable, observing similarity and equivalence of the two versions. After being corrected by the experts in the validation of the contents, the instrument was considered suitable and valid, and in the pre-test, the young people suggested some modifications to make the questionnaire more succinct. With respect to reliability, the values for the intra-class correlation coefficient were between 0.512 - acceptable and 1 - excellent and Spearman's correlation coefficient varied between 0.525 and 1, classifying the instrument as reproducible. The internal consistency was considered acceptable with a 0.757 Cronbach's alpha. The Oliveira questionnaire was choosen since it has been used in several Portuguese studies; moreover, it addresses the need to raise data regarding low back pain and associated risk factors. The Brazilian version of the Oliveira questionnaire on low back pain in young people showed valid and reliable cultural adaptation, with good reliability and stability.


Case Study: West End Quality Improvement Collaboration.
The West End Quality Improvement Collaboration is a partnership of six community health centres in Toronto that was established with the goal of increasing the efficiency and effectiveness of service delivery by working alongside one another on quality indicators. Community health centres are funded to serve the most marginalized populations, which include people living in poverty, homeless people, street-involved people, newcomers and lesbian, gay, bisexual, transgender, queer (or questioning) people. In year 1 of the initiative, we chose to focus on cancer screening rates. After the results were analyzed and we had started to see improvement in these rates, we overlaid an equity analysis to ensure that our marginalized populations were screened at similar rates. This case study will examine the steps taken to get to these outcomes and the lessons learned for collaborative practice for quality improvement. This includes understanding the importance of collaboration, including group dynamics and a culture of learning from each other, investing time and the role of expertise, all with the ultimate result of improved client care.


COMPASS: a complex of proteins associated with a trithorax-related SET domain protein.
The trithorax genes encode an evolutionarily conserved family of proteins that function to maintain specific patterns of gene expression throughout cellular development. Members of this protein family contain a highly conserved 130- to 140-amino acid motif termed the SET domain. We report the purification and molecular identification of the subunits of a protein complex in the yeast Saccharomyces cerevisiae that includes the trithorax-related protein Set1. This protein complex, which we have named COMPASS (Complex Proteins Associated with Set1), consists of seven polypeptides ranging from 130 to 25 kDa. The same seven proteins were identified in COMPASS purified either by conventional biochemical chromatography or tandem-affinity tagging of the individual subunits of the complex. Null mutants missing any one of the six nonessential subunits of COMPASS grow more slowly than wild-type cells under normal conditions and demonstrate growth sensitivity to hydroxyurea. Furthermore, gene expression profiles of strains missing either of two nonessential subunits of COMPASS are altered in similar ways, suggesting these proteins have similar roles in gene expression in vivo. Molecular characterization of trithorax complexes will facilitate defining the role of this class of proteins in the regulation of gene expression and how their misregulation results in the development of human cancer.


Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial.
To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia. A double-blind, placebo-controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4-6 weeks of flexible dose escalation followed by 12 weeks of stable-dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2-measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of "very much improved" or "much improved" on the Patient's Global Impression of Change (PGIC) scale. The 3-measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF-36) physical component summary (PCS) score. After 12 weeks of stable-dose treatment, a significantly greater proportion of milnacipran-treated patients compared with placebo-treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2-measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3-measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran-treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24-hour and weekly recall pain score, PGIC score, SF-36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo-adjusted rate of 15.8%). Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.


Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents.
We report nine consecutive children and adolescents [five females and four males; aged 2 yr 8 months (m) to 18 yr 1 m] studied over the last 5 yr with idiopathic central diabetes insipidus. In addition to vasopressin deficiency, anterior pituitary hormone deficiencies were detected, either on evaluation at presentation or during follow-up studies over the following 3 yr. Four patients had an increased concentration of plasma PRL. One patient had multiple pituitary hormone deficiencies at diagnosis, and two others developed the same by 21 m of follow-up. Brain magnestic resonance imaging scans, performed at presentation, were originally interpreted as normal in four of nine patients, except for absence of the bright posterior pituitary signal; after retrospective review, two of nine were considered normal. All of the brain magnetic resonance imaging (MRI) scans showed positive findings by 14 m of follow-up. The first abnormal finding in all patients was isolated pituitary stalk thickening. Evaluation of cerebrospinal fluid (CSF) for hCG was positive in three of eight evaluated patients; the three positive CSF values were found at presentation and 3 and 9 m after presentation. All eight patients assessed were negative for CSF alpha-fetoprotein and cytology, and no patient had serum tumor markers. Transsphenoidal biopsy of the lesion in seven of nine patients showed a germinoma in six patients and inflammatory cells in one. The six patients with documented germinoma comprise 31% of the intracranial germinomas diagnosed in this age group at the University of California-San Francisco during the last 5 yr. The patient with mononuclear inflammatory cells on biopsy along with one other patient have had spontaneous resolution of their stalk thickening. So-called "idiopathic" central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. Normal brain MRI scans or scans that show isolated pituitary stalk thickening merit follow-up with serial contrast enhanced brain MRI for the early detection of an evolving occult hypothalamic-stalk lesion. CSF evaluation is recommended at presentation because elevated CSF hCG may precede MRI abnormalities.


Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.
The two age-prevalent diseases Alzheimer disease and type 2 diabetes mellitus share many common features including the deposition of amyloidogenic proteins, amyloid β protein (Aβ) and amylin (islet amyloid polypeptide), respectively. Recent evidence suggests that both Aβ and amylin may express their effects through the amylin receptor, although the precise mechanisms for this interaction at a cellular level are unknown. Here, we studied this by generating HEK293 cells with stable expression of an isoform of the amylin receptor family, amylin receptor-3 (AMY3). Aβ1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca(2+), trigger multiple pathways involving the signal transduction mediators protein kinase A, MAPK, Akt, and cFos. Aβ1-42 and hAmylin also induce cell death during exposure for 24-48 h at low micromolar concentrations. In the presence of hAmylin, Aβ1-42 effects on HEK293-AMY3-expressing cells are occluded, suggesting a shared mechanism of action between the two peptides. Amylin receptor antagonist AC253 blocks increases in intracellular Ca(2+), activation of protein kinase A, MAPK, Akt, cFos, and cell death, which occur upon AMY3 activation with hAmylin, Aβ1-42, or their co-application. Our data suggest that AMY3 plays an important role by serving as a receptor target for actions Aβ and thus may represent a novel therapeutic target for development of compounds to treat neurodegenerative conditions such as Alzheimer disease.


Pancreatic proteases and inflammatory mediators in peritoneal fluid during splanchnic arterial occlusion and reperfusion.
Pancreatic enzymes in the ischemic intestine are involved in the production of in vivo inflammatory mediators. These mediators stimulate cells in the cardiovascular system during shock and initiate multiorgan failure. An important aspect that controls the extent of the inflammation is the dispersion of these mediators from the ischemic intestine. In the past, two pathways for dispersion of these inflammatory mediators have been identified, absorption into the intestinal venous circulation and uptake into the lymphatics. We hypothesize here that the inflammatory mediators produced by pancreatic digestive enzymes in the lumen of the intestine may also be released directly into the peritoneal space. To assess the presence of inflammatory mediators in the peritoneal cavity in response to splanchnic arterial occlusion (90 min) and reperfusion (SAO shock), we measured the ability of fluid collected from this cavity to activate naive donor granulocytes. After SAO in control rats, peritoneal lavage fluid caused activation of naive donor granulocytes when tested in vitro. In contrast, when the lumen of the small intestine was flushed with a broad-acting pancreatic enzyme inhibitor (6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate), the fluid no longer caused leukocyte activation. Reduction of the levels of inflammatory mediators in the peritoneal fluid was associated with an attenuation in the fall of blood pressure after SAO shock. These results indicate that the inflammatory mediators, which are produced by pancreatic digestive enzymes, can be absorbed directly into the systemic circulation via a transperitoneal route and play a part in the development of multiorgan failure.


Correlation between serum thyroxine and complements in patients with multiple sclerosis and neuromyelitis optica.
The aim of this study is to assess serum levels of thyroid hormones (TH) and complement C3, C4, CH50 in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO), and investigate whether there is a correlation between serum TH and complement factors in these patients. One hundred and eighty-eight MS patients and sixty-five NMO patients were included in this study. The levels of serum TH were measured by magnetic antibody enzyme linking immunoassay and complement C3, C4 and CH50 were determined by immunoturbidimetry. The levels of TT4, complement C4 and CH50 in the serum were significantly higher in NMO patients than that in the MS. There were no significant differences in serum TT3, FT3, FT4 concentrations between NMO and MS patient. In MS patients, significant correlations between mean EDSS levels and serum C3 (r=0.223, p=0.014), and serum C4 (r=0.216, p=0.017) were found, and serum TT3 was positively correlated with serum CH50 (r=0.342, p=0.01). In NMO patients, the positive association between serum FT4 and C4 (r=0.533, p=0.006) were also found. These results indicate that NMO patients has different serum TH and complement C3, C4 and CH50 levels from MS patients, and that serum TH levels is correlated with CH50 and C4 in these patients, suggesting TH may play a different role in modulating the complement activation in MS and NMO.


GABAergic interneurons in human subthalamic nucleus.
The subthalamic nucleus (STN) is considered a homogeneous structure composed essentially of projection neurons that exert a profound glutamate-mediated excitatory influence upon the main output structures of the basal ganglia. It is currently the most efficient target for deep brain stimulations designed to alleviate symptoms of Parkinson's disease. STN neurons were analyzed by applying stereological methods and single/double-immunostaining procedures to postmortem material obtained from normal individuals. Besides a multitude of closely packed projection neurons ( approximately 24.7 mum in diameter), the human STN (mean volume, 174.5 +/- 20.4 mm3; total neuronal density, 239.5 +/- 31.9 x 10(3)) contained smaller neurons (approximately 12.2 microm), which displayed glutamic acid decarboxylase (GAD)(65/67) immunoreactivity and shared the morphological features of interneurons described in Golgi studies of primate STN. These putative gamma-aminobutyric acid (GABA)ergic interneurons accounted for 7.5% of the total neuronal population of the STN. Although present throughout the nucleus, they were significantly more numerous in its posterior-ventral-medial sector, which belongs to the limbic/associative functional territory. Many projection neurons located dorsolaterally in the STN showed parvalbumin immunoreactivity and others lying ventromedially displayed calretinin immunostaining, but none of the GAD-positive interneurons expressed these calcium-binding proteins. Although less abundant than projection neurons, GABAergic interneurons might play a important role in the intrinsic organization of the STN. The morphological and chemical heterogeneity of the human STN reported here might have important implications in the functional organization of the basal ganglia.


Polygenic scores associated with educational attainment in adults predict educational achievement and ADHD symptoms in children.
The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale.


Inflammation and infection imaging with a 99mTc-neutrophil elastase inhibitor in monkeys.
A radiolabeled human neutrophil elastase inhibitor (EPI-HNE-2) may represent an improved nuclear medicine imaging agent for inflammation and infection. This peptide displays rapid pharmacokinetics due to its low molecular weight and localizes specifically on neutrophil elastase released in inflammatory sites by activated neutrophils. In this investigation, the peptide was radiolabeled with 99mTc using N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycline (NHS-MAG3) as a bifunctional chelator and was administered on 18 occasions to 5 rhesus monkeys with inflammation/infection. Plasma clearance was rapid, with liver and kidneys representing the major organs of accumulation. No evidence of toxicity, dosage effects, or circulating antiMAG3-EPI-HNE-2 antibodies was observed. Specificity of localization was established using radiolabeled bovine pancreatic trypsin inhibitor (a non-hNE-binding peptide of similar size) as a nonspecific negative control peptide and by predosing with unlabeled EPI-HNE-2 to block receptor sites before the administration of radiolabeled EPI-HNE-2. The ability of radiolabeled EPI-HNE-2 to image inflammation/infection was evaluated in 12 studies in monkeys receiving only radiolabeled EPI-HNE-2 and with lesions in the arm, shoulder, or lower back. Positive images were obtained in all studies, uptake was apparent almost immediately, and images were still positive 24 h later. As a positive control, animals also received nonspecific IgG antibody radiolabeled with 99mTc either directly or by NHS-MAG3. Compared with labeled antibody, plasma clearance of 99mTc was faster with labeled EPI-HNE-2 and accumulation in liver and heart was lower. Uptake of radioactivity in the inflammation was higher during the first hour with EPI-HNE-2 versus antibody but lower thereafter. When radiolabeled with 99mTc, EPI-HNE-2 localized specifically in inflammations in a monkey model and provided early images of diagnostic quality.


Using Text Messaging to Improve Access to Prenatal Health Information in Urban African American and Afro-Caribbean Immigrant Pregnant Women: Mixed Methods Analysis of Text4baby Usage.
The Text4baby (T4B) mobile health (mHealth) program is acclaimed to provide pregnant women with greater access to prenatal health care, resources, and information. However, little is known about whether urban African American and Afro-Caribbean immigrant pregnant women in the United States are receptive users of innovative health communication methods or of the cultural and systematic barriers that inhibit their behavioral intent to use T4B. This study aimed to understand the lived experiences of urban African American and Afro-Caribbean immigrant pregnant women with accessing quality prenatal health care and health information; to assess usage of mHealth for seeking prenatal health information; and to measure changes in participants' knowledge, perceptions, and behavioral intent to use the T4B mHealth educational intervention. An exploratory sequential mixed methods study was conducted among pregnant women and clinical professionals for a phenomenological exploration with focus groups, key informants, interviews, and observations. Qualitative themes were aligned with behavioral and information technology communications theoretical constructs to develop a survey instrument used. repeated-measures pre- and post-test design to evaluate changes in participants' knowledge, attitudes, and beliefs, of mHealth and T4B after a minimum of 4 weeks' exposure to the text message-based intervention. Triangulation and mixing of both qualitative and quantitative data occurred primarily during the survey development and also during final analysis. A total of 9 women participated in phase 1, and 49 patients signed up for T4B and completed a 31-item survey at baseline and again during follow-up. Three themes were identified: (1) patient-provider engagement, (2) social support, and (3) acculturation. With time as a barrier to quality care, inadequate patient-provider engagement left participants feeling indifferent about the prenatal care and information they received in the clinical setting. Of 49 survey participants, 63% (31/49) strongly agreed that T4B would provide them with extra support during their pregnancy. On a Likert scale of 1 to 5, participants' perception of the usefulness of T4B ranked at 4.26, and their perception of the compatibility and relative advantage of using T4B ranked at 4.41 and 4.15, respectively. At follow-up, there was a 14% increase in participants reporting their intent to use T4B and a 28% increase from pretest and posttest in pregnant women strongly agreeing to speak more with their doctor about the information learned through T4B. Urban African American and Afro-Caribbean immigrant pregnant women in Brooklyn endure a number of social and ecological determinants like low health literacy, income, and language that serve as barriers to accessing quality prenatal health care and information, which negatively impacts prenatal health behaviors and outcomes. Our study indicates a number of systematic, political, and other microsystem-level factors that perpetuate health inequities in our study population.


Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7.
What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.


The role of H-2 linked genes in helper T-cell function. IV. Importance of T-cell genotype and host environment in I-region and Ir gene expression.
We have studied the properties of helper T cells specific for sheep erythrocytes (SRBC), keyhole limpet hemocyanin (KLH), or poly-L-(Tyr,Glu)-poly-DL-Ala-poly-L-Lys [(T,G)-A--L]. These T cells differentiated and were primed in vivo in irradiation chimeras constructed of various combinations of F1 and parental bone marrow donors and irradiated recipients. Primed T cells were then tested for helper activity in the in vitro response of B cells and macrophages (Mphi) of parental or F1 origin to the hapten trinitrophenol coupled to the priming antigen. When testing either SRBC or KLH-specific T cells of parental H-2 type which had differentiated in F1 hosts, we found that they cooperated equally well with B cells and Mphi of either parental H-2 type. On the other hand, when testing F1 T cells which had differentiated in parental hosts, we found that they cooperated well only with B cells and Mphi which had the K-IA region type of the parental host. In similar experiments we found that (T,G)-A--L-specific T cells of low responder H-2 type which had differentiated in (high responder X low responder) F1 hosts induced high responses in high responder B cells and Mphi (T,G)-A--L-specific F1 T cells which differentiated in high responder but not those which differentiated in low responder hosts induced high responses in high responder B cells and Mphi. Low responder B cells and Mphi yielded low responses in all cases regardless of the source of (T,G)-A--L-specific T cells with what they were tested. Our results support the conclusion that I-region and Ir genes function via their expression in B cells and Mphi and in the host environment during helper T-cell differentiation, but not, at least under the conditions of these experiments, via their expression in the helper T cell itself. These findings place constraints upon models which attempt to explain the apparent dual recognition of antigen and I-region gene products by helper T cells.


Automated Risk Assessment for Stroke in Atrial Fibrillation (AURAS-AF)--an automated software system to promote anticoagulation and reduce stroke risk: study protocol for a cluster randomised controlled trial.
Patients with atrial fibrillation (AF) are at significantly increased risk of stroke. Oral anticoagulants (OACs) substantially reduce this risk, with gains seen across the spectrum of baseline risk. Despite the benefit to patients, OAC prescribing remains suboptimal in the United Kingdom (UK). We will investigate whether an automated software system, operating within primary care electronic medical records, can improve the management of AF by identifying patients eligible for OAC therapy and increasing uptake of this treatment. We will conduct a cluster randomised controlled trial, involving general practices using the Egton Medical Information Systems (EMIS) Web clinical system. We will randomise practices to use an electronic software tool or to continue with usual care. The tool will a) produce (and continually refresh) a list of patients with AF who are eligible for OAC therapy--practices will invite these patients to discuss therapy at the start of the trial--and b) generate electronic screen reminders in the medical records of those eligible, appearing throughout the trial. The software will run for 6 months in 23 intervention practices. A total of 23 control practices will manage their AF register in line with the usual care offered. The primary outcome is change in proportion of eligible patients with AF who have been prescribed OAC therapy after six months. Secondary outcomes are incidence of stroke, transient ischaemic attack, other major thromboembolism, major haemorrhage and reports of inappropriate OAC prescribing in the data collection sample--those deemed eligible for OACs. We will conduct a process evaluation in parallel with the randomised trial. We will use qualitative methods to examine patient and practitioner views of the intervention and its impact on primary care practice, including its time implications. AURAS-AF will investigate whether a simple intervention, using electronic primary care records, can improve OAC uptake in a high risk group for stroke. Given previous concerns about safety, especially surrounding inappropriate prescribing, we will also examine whether electronic reminders safely impact care in this clinical area. http://ISRCTN 55722437.


(Chemotaxonomic) Implications of Postharvest/Storage-Induced Changes in Plant Volatile Profiles--the Case of Artemisia absinthium L. Essential Oil.
The plant volatile profile and the essential-oil chemical composition change during the storage of plant material. The objective of this study was to develop a mathematical model able to predict, explain, and quantify these changes. Mathematical equations, derived under the assumption that the essential oil contained within plant material could be treated as an ideal solution (Raoult's law), were applied for tracking of postharvest changes in the volatile profile of Artemisia absinthium L. (the essential oils were analyzed by GC-FID and GC/MS). Starting from a specific chemical composition of an essential-oil sample obtained from plant material after a short drying period (typically 5-10 d), and by using the equations derived from this model, one could easily predict evaporation-induced changes in the volatile profile of the plant material. Based on the composition of the essential-oil sample obtained after a given storage time t, it is possible to identify those components that were involved in chemical reactions, both as reactants and possible products. The established model even allowed the recognition of pairs of transformation, i.e., 'daughter' products and their 'parent' compounds. The obtained results highlight that the essential-oil composition is highly dependent on the storage period of any plant material and urges caution in different types of phytochemical studies, especially chemotaxonomic ones, or practical application.


Thromboembolism.
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.


Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis.
Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated damage at the neuromuscular junction. Recently, the REGAIN study showed that eculizumab was effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG). However, there is no consensus regarding which kind of patients with gMG are selected to preferentially receive eculizumab. Between January and December 2018, we followed 1388 patients with MG at seven hospitals located in Tokyo and Chiba. We evaluated the clinical features of MG and the patients' quality of life. Clinical status and severity were determined by the recommendations of the Myasthenia Gravis Foundation of America. Of 1388 patients with MG, 12 (0.9%) patients received eculizumab. A total of 11 patients who were anti-acetylcholine receptor antibody-positive with refractory gMG (M:F = 3:8) completed the 26-week treatment with eculizumab. The disease subtypes represented included five cases of early onset MG, one of late-onset MG, and five of thymoma-associated MG. Overall, seven patients had experienced myasthenic crisis. The mean quantitative MG score ranged from 18.6 at baseline to 9.1 at week 26 (p = 0.008). Similarly, the mean MG activities of daily living score ranged from 10.8 at baseline to 4.2 at week 26 (p = 0.002). There were marked improvements in all patients' quality of life status. Overall, seven patients were able to reduce the dose of prednisolone at week 26. All but one patient did not require additional rescue treatment. Overall, one patient with early onset MG could not continue the eculizumab treatment due to nausea and vertigo. We demonstrate that eculizumab provided remarkable benefits for refractory gMG in practical real-world experience as well as in the REGAIN study. Patients with refractory gMG with myasthenia crisis and thymoma-associated MG are suitable for eculizumab administration.


Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.
KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.


Association of a Multifaceted Intervention With Ordering of Unnecessary Laboratory Tests Among Caregivers in Internal Medicine Departments.
Inappropriate use of laboratory testing is a challenging problem. Estimated overuse rates of approximately 20% have been reported. Effective, sustainable solutions to stimulate optimal use are needed. To determine the association of a multifaceted intervention with laboratory test volume. A before-after quality improvement study was performed between August 1, 2016, and April 30, 2018, in the internal medicine departments of 4 teaching hospitals in the Netherlands. Data on laboratory order volumes from 19 comparable hospitals were used as controls. The participants were clinicians ordering laboratory tests. The intervention included creating awareness through education and feedback, intensified supervision of residents, and changes in order entry systems. Interventions were performed by local project teams and guided by a central project team during a 6-month period. Sustainability was investigated during an 8-month follow-up period. The primary outcome was the change in slope for laboratory test volume. Secondary outcomes were change in slope for laboratory expenditure, order volumes and expenditure for other diagnostic procedures, and clinical outcomes. Data were collected on duration of hospital stay, rate of repeated outpatient visits, 30-day readmission rate, and rate of unexpected prolonged duration of hospital stay for patients admitted for pneumonia. The numbers of internists and residents ordering tests in hospitals 1 to 4 were 16 and 30, 18 and 20, 13 and 17, and 21 and 60, respectively. Statistically significant changes in slope for laboratory test volume per patient contact were found at hospital 1 (change in slope, -1.55; 95% CI, -1.98 to -1.11; P < .001), hospital 3 (change in slope, -0.74; 95% CI, -1.42 to -0.07; P = .03), and hospital 4 (change in slope, -2.18; 95% CI, -3.27 to -1.08; P < .001). At hospital 2, the change in slope was not statistically significant (-0.34; 95% CI, -2.27 to 1.58; P = .73). Laboratory test volume per patient contact decreased by 11.4%, whereas the volume increased by 2.4% in 19 comparable hospitals. Statistically significant changes in slopes for laboratory costs and volumes and costs for other diagnostic procedures were also observed. Clinical outcomes were not associated with negative changes. Important facilitators were education, continuous attention for overuse, feedback, and residents' involvement. Important barriers were difficulties in data retrieval, difficulty in incorporation of principles in daily practice, and high resident turnover. A set of interventions aimed at changing caregivers' mindset was associated with a reduction in the laboratory test volume in all departments, whereas the volume increased in comparable hospitals in the Netherlands. This study provides a framework for nationwide implementation of interventions to reduce unnecessary laboratory testing.


Neuronal voltage-gated sodium channel subtypes: key roles in inflammatory and neuropathic pain.
Voltage-gated sodium channels (VGSCs) play an important role in neuronal excitability. Regulation of VGSC activity is a complex phenomenon that occurs at multiple levels in the cell, including transcriptional regulation, post-translational modification and membrane insertion and retrieval. Multiple VGSC subtypes exist that vary in their biophysical and pharmacological properties and tissue distribution. Any alteration of the VGSC subtype profile of a neuron or the mechanisms that regulate VGSC activity can cause significant changes in neuronal excitability. Inflammatory and neuropathic pain states are characterised by alterations in VGSC subtype composition and activity in sensory neurons. This review focuses on the VGSC subtypes involved in such pain states.


The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive.
The functional architecture of prefrontal cortex is central to our understanding of human mentation and cognitive prowess. This region of the brain is often treated as an undifferentiated structure, on the one hand, or as a mosaic of psychological faculties, on the other. This paper focuses on the working memory processor as a specialization of prefrontal cortex and argues that the different areas within prefrontal cortex represent iterations of this function for different information domains, including spatial cognition, object cognition and additionally, in humans, semantic processing. According to this parallel processing architecture, the 'central executive' could be considered an emergent property of multiple domain-specific processors operating interactively. These processors are specializations of different prefrontal cortical areas, each interconnected both with the domain-relevant long-term storage sites in posterior regions of the cortex and with appropriate output pathways.


Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons.
Membrane excitability in different tissues is due, in large part, to the selective expression of distinct genes encoding the voltage-dependent sodium channel. Although the predominant sodium channels in brain, skeletal muscle, and cardiac muscle have been identified, the major sodium channel types responsible for excitability within the peripheral nervous system have remained elusive. We now describe the deduced primary structure of a sodium channel, peripheral nerve type 1 (PN1), which is expressed at high levels throughout the peripheral nervous system and is targeted to nerve terminals of cultured dorsal root ganglion neurons. Studies using cultured PC12 cells indicate that both expression and targeting of PN1 is induced by treatment of the cells with nerve growth factor. The preferential localization suggests that the PN1 sodium channel plays a specific role in nerve excitability.


Capillary origami: spontaneous wrapping of a droplet with an elastic sheet.
The interaction between elasticity and capillarity is used to produce three-dimensional structures through the wrapping of a liquid droplet by a planar sheet. The final encapsulated 3D shape is controlled by tailoring the initial geometry of the flat membrane. Balancing interfacial energy with elastic bending energy provides a critical length scale below which encapsulation cannot occur, which is verified experimentally. This length is found to depend on the thickness as h3/2, a scaling favorable to miniaturization which suggests a new way of mass production of 3D micro- or nanoscale objects.


Physician-elder interaction in community family practice.
To determine whether outpatient visits by elders seeing community family physicians differ in length or content from visits by younger patients; socioemotional preferences predict visit content; and satisfaction correlates with visit content differentially across age. In a multimethod cross-sectional study of 84 community family practices in northeastern Ohio, 3453 adult patient visits with 138 community family physicians were observed; 2362 of these patients completed self-report questionnaires. Three age groups were compared: 18 to 64, 65 to 74, and over 74 years. Length and content of the physician-patient encounter was determined using the Davis Observation Code (DOC); satisfaction was assessed using the MOS 9-item Visit Rating Scale. Controlling for reason for visit and demographics, visit length averaged 10.7 minutes for each group. Visit content differed significantly on 13 of 20 DOC codes between one of the older groups and the younger group; in 4 instances, content varied between the 2 older groups. Although visit content varied as predicted by socioemotional theory, no consistent patterns of association between visit content and satisfaction emerged. Older patient visits differ from those of younger patients as might be predicted by socioemotional selectivity theory; however, there was little association of visit content with patient satisfaction.