Implications of Lifecourse Epidemiology for Research on Determinants of Adult Disease.
Many diseases commonly associated with aging are now thought to have social and physiologic antecedents in early life. Understanding how the timing of exposure to early life risk factors influences later-life health may illuminate mechanisms driving adult health inequalities and identify possible points for effective interventions. Recognizing chronic diseases as developing across the lifecourse also has implications for the conduct of research on adult risk factors for disease. We review alternative conceptual models that describe how the timing of risk factor exposure relates to the development of disease. We propose some expansions of lifecourse models to improve their relevance for research on adult chronic disease, using the relationship between education and adult cognitive decline and dementia as an example. We discuss the important implications each of the lifecourse conceptual models has on study design, analysis, and interpretation of research on aging and chronic diseases. We summarize several research considerations implied by the lifecourse framework, including: advantages of analyzing change in function rather than onset of impairment; the pervasive challenge of survivor bias; the importance of controlling for possible confounding by early life conditions; and the likely heterogeneity in responses of adults to treatment.


Effect of a near-universal hospitalization-based prophylaxis regimen on annual number of venous thromboembolism events in the US.
The annual number of US venous thromboembolism (VTE) events, the number of potentially preventable events, and the effect of hospitalization-based prophylaxis are uncertain. We estimated VTE attack (incident plus recurrent VTE) rates and the total annual number of US VTE events related and unrelated to hospitalization using Rochester Epidemiology Project resources to identify all Olmsted County, Minnesota, residents with incident or recurrent VTE over the 6-year period 2005-2010. The average annual VTE attack rates related and unrelated to hospitalization were 282 and 8 per 10 000 person-years, respectively. The estimated average number of US VTE events was 495 669 per year (48% unrelated to hospitalization). Among Olmsted County residents hospitalized at a Mayo Clinic hospital from 2005 to 2010, the proportion of patients receiving VTE prophylaxis or with an indication that prophylaxis was unnecessary increased from ∼40% in 2005 to ∼90% by 2010. The annual age- and sex-adjusted hospitalization-related (in-hospital) VTE attack rates from 2005 to 2010 ranged from 251 to 306 (1155 to 1751) per 10 000 person-years (bed-years) and did not change significantly. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively. A total of 75% of VTE events occurred after hospital discharge, with a 19.5-day median time to VTE. Additional efforts are needed to identify the individual inpatient and outpatient at high risk for incident and recurrent VTE and target (longer duration) primary and secondary prophylaxis to high-risk individuals who would benefit most.


EBNA1 IgM-Based Discrimination Between Rheumatoid Arthritis Patients, Systemic Lupus Erythematosus Patients and Healthy Controls.
Epstein-Barr Virus (EBV) has been associated with development of rheumatic connective tissue diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in genetically susceptible individuals. Diagnosis of RA and SLE relies on clinical criteria in combination with the presence of characteristic autoantibodies. In addition, antibodies to several EBV antigens have been shown to be elevated in patients with these diseases compared to healthy controls (HC). Here, we elaborated improved enzyme-linked immunosorbent assays for antibodies (IgM, IgA, IgG) to the EBV proteins Epstein-Barr Virus nuclear antigen (EBNA)1 and early antigen diffuse (EAD) in order to determine their potential diagnostic role. We showed that especially EBNA1 IgM distinguished RA from SLE and HCs and also distinguished SLE from HCs. EBNA1 IgA was almost as effective in differentiating RA from SLE and HC, while EAD IgG and IgA were able to discern SLE patients from RA patients and HCs. Collectively, these findings illustrate the potential diagnostic use of antibodies to EBV proteins to diagnose RA and to differentiate SLE from RA.


Mortality among Icelandic nurses.
The goal of the study was to investigate the mortality pattern of female nurses in a retrospective cohort study with special focus on suicide. The mortality of nurses was compared with that of the general female population. The main outcome measure was the standardized mortality ratio (SMR). The participants were 2159 female nurses (ie, all registered nurses in Iceland between 1920-1979). A long-lasting healthy worker effect was found in the cohort. A moderate excess of suicide was observed. A deficit was found for stomach cancer, ischemic heart disease, and respiratory disease. When the cohort was divided according to employment time, there was an excess of brain cancer among those with an employment time of less than 20 years, and all the suicides occurred in that group. The deficit of ischemic heart disease and respiratory disease was more pronounced in the group employed more than 20 years. It was concluded that nurses, primarily those with a long employment time, enjoy the benefits of their initial good health, but the moderate excess of suicide could be associated with stress and frustration, which the nurses relate to their work situation.


Kinematic changes during the cryopreservation of boar spermatozoa.
The present study evaluates the effect that various steps of a conventional cycle of cryopreservation have on the patterns of movement exhibited by boar spermatozoa. Sperm-rich ejaculate fractions collected from 24 mature fertile boars (1 ejaculate per boar) were cryopreserved following a standard freeze-thaw procedure with 0.5-mL plastic straws. Overall sperm motility and the individual kinematic parameters of motile spermatozoa (assessed by the computer-aided sperm analysis system Sperm Class Analyzer [SCA]) were recorded in 5 steps of the cryopreservation procedure. These steps were as follows: 1) at the time that the fresh semen was extended, 2) at 17 degrees C, after sperm concentration by centrifugation and re-extension of the pellet with lactose-egg yolk extender; 3) at 5 degrees C, after added freezing extender; 4) at the time that thawed semen was held in a water bath at 37 degrees C for 30 minutes; and 5) at the time that thawed semen was held in a water bath at 37 degrees C for 150 minutes. Data from individual motile spermatozoa, defined by 7 kinematic parameters (curvilinear velocity [VCL], straight-line velocity [VSL], average path velocity [VAP], linearity [LIN], straightness [STR], mean amplitude of lateral head displacement [ALH], and beat cross frequency [BCF]), were analyzed using a pattern analysis technique (PATN) to identify and quantify populations and subpopulations of motile sperm within the semen samples. After the first cluster analysis, 3 motile sperm populations (P) were identified (P1: progressive and/or vigorous cells [90.4%], P2: poorly progressive cells [8.3%], and P3: nonprogressive cells [1.3%]). These populations remained constant (P > .05) throughout the 5-step cryopreservation procedure. A second PATN was carried out within the P1 sperm population, which identified 3 sperm subpopulations (sP) (eg, sP1: cells with progressive and vigorous movement [58.7%], sP2: progressive cells only [24.6%], and sP3: vigorous cells only, hyperactive-like [16.7%]). Although the relative frequency of these 3 subpopulations varied among ejaculates (boars), there was no interaction with any cryopreservation step we examined. Whereas sP1 remained constant (P > .05), sP2 and sP3 varied significantly (P < .05) through the cryopreservation procedure, with the increase in sP3 after centrifugation at 17 degrees C and during cooling at 5 degrees C considered particularly relevant. In conclusion, the present study confirms the heterogeneity of sperm movement patterns in boar semen, patterns that vary through the cryopreservation procedure, especially after removal of the seminal plasma by centrifugation and subsequent extension at 17 degrees C and after the slow cooling at 5 degrees C, when obvious increases in hyperactivated movement appeared. The vast majority of spermatozoa, those exhibiting progressive and vigorous movement, remained constant during the cryopreservation procedure, although the proportion differed among boars.


Effect of soybean (Glycine max L.) on the hormonal milieu of male rats.
Effect of soybean (Glycine max) on serum level of some sex hormones: testosterone, follicle stimulating hormone (FSH), luteinizing hormone/interstitial cell stimulating hormone (LH/ICSH), estradiol and prolactin in male rats was investigated. Twenty male albino rats of 12 weeks old with similar body weights were assigned to four groups of 5 rats each and treatment with soybean meal at 100, 200 and 300 mg kg(-1) body weight, respectively daily for 8 weeks. Blood samples collected through cardiac puncture were assayed for levels of hormones. There were dose-dependent effects of the soybean meal on the serum concentration of the hormones. The treatment significantly reduced the levels of testosterone and FSH in the serum while it significantly increased the levels of estradiol, LH/ICSH and prolactin. The results show that soybean (Glycine max) had strong capability to disrupt hormonal functions. Hence, its indiscriminate use could increase the risk of infertility in males.


Early discharge after primary percutaneous coronary intervention for ST-elevation myocardial infarction.
To assess safety of early discharge following primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). Retrospective analysis of prospectively collected data of 2448 STEMI patients treated with PPCI surviving to hospital discharge. Post-discharge all-cause mortality was reported at 1, 7, and 30 days and long-term follow up. A total of 1542 patients (63.0%) were discharged within 2 days of admission (early discharge group) and 906 patients (37.0%) after 2 days (late discharge group). In both groups, no deaths were recorded 1 day post discharge. The early and late discharge group mortality figures for 7 days were 0 and 4 patients (0.04%) and between 7 and 30 days were 11 (0.7%) and 11 patients (1.2%), respectively. During a mean follow up of 584 days, 178 patients (7.3%) died: 67 in the early discharge group (4.3%) and 111 in the late discharge group (12.3%). This exploratory, observational study demonstrates that discharging low-risk STEMI patients within 2 days following PPCI is safe. For providers of health care, early discharge can help to allay the cost of providing a 24-hour PPCI service and adds to the recognized benefits arising from PPCI.


Bedouin wives on the home front: living with men serving in the Israel Defense Forces.
This community-based study examined emotional and somatic symptoms of 129 Bedouin women whose husbands serve in the Israel Defense Forces. Wives of men diagnosed with posttraumatic stress disorder (PTSD) reported more symptoms than wives of men diagnosed with other disorders and wives of men with no diagnosis. Findings indicate that not only was PTSD in Bedouin servicemen positively associated with their wives' symptoms of posttraumatic stress and depression and somatic complaints, but that this relationship was fully mediated by husbands' aggression. Unraveling the special circumstances of women from traditional backgrounds faced with the devastating effects of husbands' combat-related posttraumatic pathology may inform an approach to the concept of vicarious trauma that is more specific to non-Western societies.


Newcastle disease virus as an oncolytic agent.
Cancer is a major cause of deaths in humans. Though there has been significant progress in cancer therapy, the limited efficacy and toxicities of current chemo- and radiotherapies have provided an impetus for the search of new therapeutics. A therapeutic approach, which uses viruses for the treatment of cancer termed, oncolytic virotherapy has recently emerged. Newcastle disease virus (NDV) is one such virus with an inherent oncolytic property. NDV causes a highly infectious disease in poultry worldwide. In humans it is reported to have oncolytic and immuno-stimulatory effects. It specifically replicates in tumour cells while sparing normal cells and cause oncolysis. For many years different strains of the NDV have been investigated for treatment of various human cancers. Recent advances in reverse genetics provided investigators the tools to produce recombinant NDV with improved oncolytic property.


PKM2, cancer metabolism, and the road ahead.
A major metabolic aberration associated with cancer is a change in glucose metabolism. Isoform selection of the glycolytic enzyme pyruvate kinase has been implicated in the metabolic phenotype of cancer cells, and specific pyruvate kinase isoforms have been suggested to support divergent energetic and biosynthetic requirements of cells in tumors and normal tissues. PKM2 isoform expression has been closely linked to embryogenesis, tissue repair, and cancer. In contrast, forced expression of the PKM1 isoform has been associated with reduced tumor cell proliferation. Here, we discuss the role that PKM2 plays in cells and provide a historical perspective for how the study of PKM2 has contributed to understanding cancer metabolism. We also review recent studies that raise important questions with regard to the role of PKM2 in both normal and cancer cell metabolism.


The Vulcan Version 3.0 High-Resolution Fossil Fuel CO2 Emissions for the United States.
Estimates of high-resolution greenhouse gas (GHG) emissions have become a critical component of climate change research and an aid to decision makers considering GHG mitigation opportunities. The "Vulcan Project" is an effort to estimate bottom-up carbon dioxide emissions from fossil fuel combustion and cement production (FFCO2) for the U.S. landscape at space and time scales that satisfy both scientific and policy needs. Here, we report on the Vulcan version 3.0 which quantifies emissions at a resolution of 1 km2/hr for the 2010-2015 time period. We estimate 2011 FFCO2 emissions of 1,589.9 TgC with a 95% confidence interval of 1,367/1,853 TgC (-14.0%/+16.6%), implying a one-sigma uncertainty of ~ ±8%. Per capita emissions are larger in states dominated by electricity production and industrial activity and smaller where onroad and building emissions dominate. The U.S. FFCO2 emissions center of mass (CoM) is located in the state of Missouri with mean seasonality that moves on a near-elliptical NE/SW path. Comparison to ODIAC, a global gridded FFCO2 emissions estimate, shows large total emissions differences (100.4 TgC for year 2011), a spatial correlation of 0.68 (R2), and a mean absolute relative difference at the 1 km2 scale of 104.3%. The Vulcan data product offers a high-resolution estimate of FFCO2 emissions in every U.S. city, obviating costly development of self-reported urban inventories. The Vulcan v3.0 annual gridded emissions data product can be downloaded from the Oak Ridge National Laboratory Distributed Active Archive Center (Gurney, Liang, et al., 2019, https://doi.org/10.3334/ORNLDAAC/1741).


Cognitive rehabilitation and problem-solving to improve quality of life of patients with primary brain tumors: a pilot study.
Caregivers of patients with brain tumors frequently identify cognitive impairment in their loved ones as their greatest burden, but only one published study has examined a cognitive-rehabilitation intervention for adults with brain tumors. Emotional distress and poor quality of life (QOL) also have been identified as important issues, yet they have been excluded from most intervention studies that target coping and mood. The primary aim of this pilot study was to determine the feasibility and tolerability of a combined cognitive-rehabilitation and problem-solving-therapy intervention for patients with brain tumors and their caregivers. In all, 19 patient/caregiver pairs were enrolled and randomized, and 13 pairs completed the 2-week trial. After receiving the intervention, 88% of patients used the study-specific strategies, and 88% indicated that they would recommend the intervention to other patients diagnosed with a brain tumor. The study intervention was described as "very helpful" or "somewhat helpful" by 88% of study participants. Caregivers were similarly enthusiastic about the intervention. The results showed that patients with brain tumors who have cognitive impairment can participate meaningfully in a structured intervention, and they supported further research into the potential effectiveness of formal rehabilitation targeting cognitive and QOL symptoms for patients with brain tumors and their caregivers.


Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia.
To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.


Trends in the clinical characteristics of HIV-infected patients initiating antiretroviral therapy in Kenya, Uganda and Tanzania between 2002 and 2009.
East Africa has experienced a rapid expansion in access to antiretroviral therapy (ART) for HIV-infected patients. Regionally representative socio-demographic, laboratory and clinical characteristics of patients accessing ART over time and across sites have not been well described. We conducted a cross-sectional analysis of characteristics of HIV-infected adults initiating ART between 2002 and 2009 in Kenya, Uganda and Tanzania and in the International Epidemiologic Databases to Evaluate AIDS Consortium. Characteristics associated with advanced disease (defined as either a CD4 cell count level of less than 50 cells/mm3 or a WHO Stage 4 condition) at the time of ART initiation and use of stavudine (D4T) or nevirapine (NVP) were identified using a log-link Poisson model with robust standard errors. Among 48,658 patients (69% from Kenya, 22% from Uganda and 9% from Tanzania) accessing ART at 30 clinic sites, the median age at the time of ART initiation was 37 years (IQR: 31-43) and 65% were women. Pre-therapy CD4 counts rose from 87 cells/mm3 (IQR: 26-161) in 2002-03 to 154 cells/mm3 (IQR: 71-233) in 2008-09 (p<0.001). Accessing ART at advanced disease peaked at 35% in 2005-06 and fell to 27% in 2008-09. D4T use in the initial regimen fell from a peak of 88% in 2004-05 to 59% in 2008-09, and a greater extent of decline was observed in Uganda than in Kenya and Tanzania. Self-pay for ART peaked at 18% in 2003, but fell to less than 1% by 2005. In multivariable analyses, accessing ART at advanced immunosuppression was associated with male sex, women without a history of treatment for prevention of mother to child transmission (both as compared with women with such a history) and younger age after adjusting for year of ART initiation and country of residence. Receipt of D4T in the initial regimen was associated with female sex, earlier year of ART initiation, higher WHO stage, and lower CD4 levels at ART initiation and the absence of co-prevalent tuberculosis. Public health ART services in east Africa have improved over time, but the fraction of patients accessing ART with advanced immunosuppression is still high, men consistently access ART with more advanced disease, and D4T continues to be common in most settings. Strategies to facilitate access to ART, overcome barriers among men and reduce D4T use are needed.


What the eyes say about planning of focused referents during sentence formulation: a cross-linguistic investigation.
This study investigated how sentence formulation is influenced by a preceding discourse context. In two eye-tracking experiments, participants described pictures of two-character transitive events in Dutch (Experiment 1) and Chinese (Experiment 2). Focus was manipulated by presenting questions before each picture. In the Neutral condition, participants first heard "What is happening here?" In the Object or Subject Focus conditions, the questions asked about the Object or Subject character (What is the policeman stopping? Who is stopping the truck?). The target response was the same in all conditions (The policeman is stopping the truck). In both experiments, sentence formulation in the Neutral condition showed the expected pattern of speakers fixating the subject character (policeman) before the object character (truck). In contrast, in the focus conditions speakers rapidly directed their gaze preferentially only to the character they needed to encode to answer the question (the new, or focused, character). The timing of gaze shifts to the new character varied by language group (Dutch vs. Chinese): shifts to the new character occurred earlier when information in the question can be repeated in the response with the same syntactic structure (in Chinese but not in Dutch). The results show that discourse affects the timecourse of linguistic formulation in simple sentences and that these effects can be modulated by language-specific linguistic structures such as parallels in the syntax of questions and declarative sentences.


Complementary value of cardiac FDG PET and CT for the characterization of atherosclerotic disease.
For decades, the identification of significant luminal narrowing has been the hallmark to characterize the presence and extent of coronary artery disease. However, it is now known that characterizations of systemic atherosclerosis burden and inflammation, as well as the local quality of plaque composition and morphology, allow better characterization of coronary artery disease and thus may allow improved prediction of adverse cardiovascular events. Plaque characterized histologically as a thin-cap fibroatheroma (ie, an atheroma with a thin fibrous cap, an underlying lipid-rich necrotic core, and inflammatory activity) has been recognized as representing vulnerable or high-risk plaque. Positron emission tomography (PET) and cardiac computed tomography (CT) are noninvasive modalities that provide metabolic (PET) and morphologic (CT) information about atherosclerotic plaque. PET allows the quantification of the uptake of fluorine 18 fluorodeoxyglucose (FDG) within the arterial wall, which provides a measure of macrophage activity within atheromatous plaque. Coronary CT allows the depiction of plaque morphology and composition. Thus, integrated imaging with PET and CT (PET/CT) permits coregistration of FDG activity with the presence and morphology of plaque and may lead to improved characterization of vulnerable plaque or vulnerable patients, or both. This review details the methods and principles of cardiac FDG PET and coronary CT and provides an overview of the research, with an emphasis on the identification and characterization of vulnerable plaque.


Immune response and insulin signalling alter mosquito feeding behaviour to enhance malaria transmission potential.
Malaria parasites alter mosquito feeding behaviour in a way that enhances parasite transmission. This is widely considered a prime example of manipulation of host behaviour to increase onward transmission, but transient immune challenge in the absence of parasites can induce the same behavioural phenotype. Here, we show that alterations in feeding behaviour depend on the timing and dose of immune challenge relative to blood ingestion and that these changes are functionally linked to changes in insulin signalling in the mosquito gut. These results suggest that altered phenotypes derive from insulin signalling-dependent host resource allocation among immunity, blood feeding, and reproduction in a manner that is not specific to malaria parasite infection. We measured large increases in mosquito survival and subsequent transmission potential when feeding patterns are altered. Leveraging these changes in physiology, behaviour and life history could promote effective and sustainable control of female mosquitoes responsible for transmission.


Matching phenotypes to whole genomes: Lessons learned from four iterations of the personal genome project community challenges.
The advent of next-generation sequencing has dramatically decreased the cost for whole-genome sequencing and increased the viability for its application in research and clinical care. The Personal Genome Project (PGP) provides unrestricted access to genomes of individuals and their associated phenotypes. This resource enabled the Critical Assessment of Genome Interpretation (CAGI) to create a community challenge to assess the bioinformatics community's ability to predict traits from whole genomes. In the CAGI PGP challenge, researchers were asked to predict whether an individual had a particular trait or profile based on their whole genome. Several approaches were used to assess submissions, including ROC AUC (area under receiver operating characteristic curve), probability rankings, the number of correct predictions, and statistical significance simulations. Overall, we found that prediction of individual traits is difficult, relying on a strong knowledge of trait frequency within the general population, whereas matching genomes to trait profiles relies heavily upon a small number of common traits including ancestry, blood type, and eye color. When a rare genetic disorder is present, profiles can be matched when one or more pathogenic variants are identified. Prediction accuracy has improved substantially over the last 6 years due to improved methodology and a better understanding of features.


Systems biology discoveries using non-human primate pluripotent stem and germ cells: novel gene and genomic imprinting interactions as well as unique expression patterns.
The study of pluripotent stem cells has generated much interest in both biology and medicine. Understanding the fundamentals of biological decisions, including what permits a cell to maintain pluripotency, that is, its ability to self-renew and thereby remain immortal, or to differentiate into multiple types of cells, is of profound importance. For clinical applications, pluripotent cells, including both embryonic stem cells and adult stem cells, have been proposed for cell replacement therapy for a number of human diseases and disorders, including Alzheimer's, Parkinson's, spinal cord injury and diabetes. One challenge in their usage for such therapies is understanding the mechanisms that allow the maintenance of pluripotency and controlling the specific differentiation into required functional target cells. Because of regulatory restrictions and biological feasibilities, there are many crucial investigations that are just impossible to perform using pluripotent stem cells (PSCs) from humans (for example, direct comparisons among panels of inbred embryonic stem cells from prime embryos obtained from pedigreed and fertile donors; genomic analysis of parent versus progeny PSCs and their identical differentiated tissues; intraspecific chimera analyses for pluripotency testing; and so on). However, PSCs from nonhuman primates are being investigated to bridge these knowledge gaps between discoveries in mice and vital information necessary for appropriate clinical evaluations. In this review, we consider the mRNAs and novel genes with unique expression and imprinting patterns that were discovered using systems biology approaches with primate pluripotent stem and germ cells.


A Literature Review and Gap Analysis of Emerging Technologies and New Trends in Gambling.
There have been significant changes in the gambling landscape particularly relating to gambling in the digital age. As the gambling landscape changes, regulation of gambling also needs to change. In 2018, the Office of Responsible Gambling in New South Wales, Australia, commissioned a gap analysis to inform their research objectives and priority focus areas. This included an identification of gaps in our understanding of emerging technologies and new trends in gambling. A gap analysis of the peer-reviewed literature published since 2015 was undertaken, identifying 116 articles. The main area of focus was Internet gambling, followed by articles exploring the relationship between video gaming and gambling, the expansion of the sports betting market, Electronic Gambling Machines characteristics and articles exploring new technologies and trends in advertising and inducements. Key gaps related to the need for more research in general, as well as research focusing on subpopulations such as those using different gambling formats, those with varying levels of problem gambling, and vulnerable populations. From a methods perspective, researchers saw the need for longitudinal studies, more qualitative research and improved outcome measures. The development and testing of a public health approach to addressing the harms associated with gambling in these areas is needed.


Chronic pedunculopontine nucleus stimulation restores functional connectivity.
The mechanisms of deep brain stimulation (DBS) are poorly understood. Earlier, high-frequency DBS has been thought to represent a depolarization block of the target area and low-frequency stimulation has been thought to 'drive' neuronal activity. We investigated the long-term effect of low-frequency DBS in a longitudinal imaging study of a patient who received bilateral pedunculopontine nucleus stimulation. We used the diffusion tensor imaging techniques including probabilistic tractography and topographic mapping to analyze long-term changes in connectivity with low-frequency DBS. Post-DBS connectivity analysis suggested a normalization of pathological pedunculopontine nucleus connectivity with DBS therapy. These findings may help elucidate the mechanisms of DBS, suggesting neuroplasticity involving a reorganization of target connectivity long term. This is the first reported case showing neuroimaging evidence of neuroplasticity after low-frequency DBS.


Effect of severe dietary magnesium deficiency on systemic bone density and removal torque of osseointegrated implants.
This study evaluated the effect of severe magnesium (Mg) dietary deficiency on systemic bone density and biomechanical resistance of bone tissue to the removal torque of osseointegrated implants. The sample consisted of 45 rats; each received a titanium implant in their tibial metaphysis. After 60 days, the animals were divided into three groups (n = 15) according to their dietary Mg: the control group received the recommended content of Mg, group Mg1 received a 75% reduction in dietary Mg content, and group Mg2 was fed a diet with a 90% reduction in Mg content. Animals were sacrificed 150 days after implant placement. Serum concentrations of Mg were measured and the effect of Mg deficiency on systemic bone density was evaluated by densitometry of the lumbar vertebrae and femur. Biomechanical characteristics were measured by resistance of the bone tissue to removal of the implants. Lower Mg serum concentrations were found for the Mg1 and Mg2 groups; however, densitometric analysis and torque evaluations showed a statistically significant difference only in the Mg2 group (P < .05). There was a statistically significant difference in removal torque between the Mg2 group and the control group. This study showed that a severe deficiency of Mg decreased the systemic bone density and removal torque of osseointegrated implants.


Structure of the ATP-binding domain of Plasmodium falciparum Hsp90.
Hsp90 is an important cellular chaperone and attractive target for therapeutics against both cancer and infectious organisms. The Hsp90 protein from the parasite Plasmodium falciparum, the causative agent of malaria, is critical for this organism's survival; the anti-Hsp90 drug geldanamycin is toxic to P. falciparum growth. We have solved the structure of the N-terminal ATP-binding domain of P. falciparum Hsp90, which contains a principal drug-binding pocket, in both apo and ADP-bound states at 2.3 A resolution. The structure shows that P. falciparum Hsp90 is highly similar to human Hsp90, and likely binds agents such as geldanamycin in an identical manner. Our results should aid in the structural understanding of Hsp90-drug interactions in P. falciparum, and provide a scaffold for future drug-discovery efforts.


Monk-gillieson monochromator.
The theory developed by Seya, Namioka, and Sai has been numerically evaluated with the purpose of furnishing practical data for designing a Monk-Gillieson monochromator, in which coma-type aberration is eliminated at one specific wavelength of the designer's choice. The numerical results are conveniently arranged in the form of graphs and tables so as to facilitate estimation of the optimum instrumental constants and the performance to be expected. The calculations included here have been verified experimentally with a monochromator whose instrumental constants were so chosen, in accordance with the theory, as to eliminate the coma-type aberration at 3000 A. For practical interest, the performance of the above monochromator has also been compared with that of a Schroeder-type monochromator.


Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula.
Carotid cavernous fistulas are abnormal communications between the cavernous sinus and the external or internal carotid arteries. Although rare, closure of carotid cavernous fistulas can lead to immediate ocular complications. To our knowledge, our case represents the first report of worsening angle closure glaucoma and choroidal detachments over an extended period of two months subsequent to closure of a carotid cavernous fistula. A 70-year-old female with a history of primary angle closure glaucoma presented with 4 mm of proptosis, resistance to retropulsion, tortuous corkscrew blood vessels and an orbital bruit of the right eye. Diagnostic cerebral angiogram showed a small indirect Barrow type D right carotid cavernous fistula. Transarterial embolization was planned but repeat cerebral angiography prior to the procedure demonstrated spontaneous partial closure of the carotid cavernous fistula and the procedure was aborted. One month later, our patient was noted to have worsening vision and choroidal detachments of the right eye. She declined further testing and was thus started on self-administered manual carotid jugular compressions. One month later, she developed progressive worsening of her choroidal detachments and angle closure. She eventually opted for surgical intervention but repeat cerebral angiography showed significant thrombosis of the carotid cavernous fistula and no intervention was warranted. Examination two months later showed complete resolution of the choroidal detachments and open angles of both eyes. Our patient demonstrated worsening angle closure glaucoma and choroidal detachments after spontaneous closure of her carotid cavernous fistula had been noted. Ocular complications, including acute angle closure, have been reported to occur immediately after closure of carotid cavernous fistulas, but not over months as in our patient. It is imperative that individuals who have undergone apparent closure of a carotid cavernous fistula be carefully monitored for worsening ocular complications.


Topical application of 1-methylnicotinamide in the treatment of rosacea: a pilot study.
Rosacea is a chronic facial dermatosis with a progressive course, which is characterized by the presence of erythema, papules, pustules, telangiectasias and sebaceous gland hyperplasia. However, the aetiology is still unknown; genetic predisposition, gastrointestinal disorders (Helicobacter pylori), infestations with Demodex folliculorum and environmental stimuli are considered to be involved in the inflammatory process. A metabolite of nicotinamide, 1-methylnicotinamide (MNA(+)), has anti-inflammatory properties, and this is the first study to test the effectiveness of this agent in treating rosacea. In total, 34 patients with rosacea were treated with a gel containing 0.25% MNA(+) as a chloride salt, twice daily for 4 weeks, after which improvement was observed in 26/34 cases. The improvement was good in 9/34 and moderate in 17/34, but no clinical effect was noted in seven subjects. In only one case was skin irritation given as the reason for treatment withdrawal. These results indicate that MNA(+) might be a useful agent for treating rosacea.


Macrophages ingest and are activated by bacterial DNA.
Recent evidence suggests that bacterial DNA activates immune responses. Here we showed that TNF-alpha mRNA was induced in bone marrow-derived macrophages and the macrophage cell line RAW 264 by plasmid DNA, but not by DNaseI-digested plasmid, plasmid methylated on CpG dinucleotides, or by vertebrate genomic DNA, which is naturally largely methylated on these sequences. Synthetic polynucleotides poly d(I-C) and poly I x poly C also induced TNF-alpha. IL-1 beta and plasminogen activator inhibitor-2 mRNAs were induced by plasmid DNA, and IFN-gamma-pretreated macrophages responded to DNA with induction of inducible nitric oxide synthase. The HIV-1 long terminal repeat was activated by exogenous DNA in a manner similar to TNF-alpha, and was also activated by a CpG-containing oligonucleotide. Transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of the HIV-1 long terminal repeat and many inflammatory response genes. NF-kappa B binding activity was increased by plasmid DNA. An important question is whether these effects involve DNA binding to a cell surface receptor that signals to the interior, or whether internalization is necessary. Here we found that plasmid was taken up by RAW 264 cells and remained sufficiently intact to code for luciferase protein. Results suggest that DNA is taken up by macrophages and characteristic bacterial DNA sequences, which include an unmethylated CpG sequence, activate a signaling cascade leading to activation of NF-kappa B and inflammatory gene induction. Relevance to DNA vaccination, gene therapy, antisense, and transfection studies is discussed.


Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline.
This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL-1 to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL-1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4-5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.


Trajectories of quality of life, life satisfaction, and psychological adjustment after prostate cancer.
To describe trajectories of health-related quality of life (QoL), life satisfaction, and psychological adjustment for men with prostate cancer over the medium to long term and identify predictors of poorer outcomes using growth mixture models. One-thousand sixty-four (82.4% response) men diagnosed with prostate cancer were recruited close to diagnosis and assessed over a 72-month (6-year) period with self-report assessment of health-related QoL, life satisfaction, cancer-related distress, and prostate specific antigen anxiety. Urinary, bowel, and sexual function were also assessed using validated questionnaires. Poorer physical QOL was predicted by older age, lower education, lower income, comorbidities, and receiving hormone therapy. Lower life satisfaction was related to younger age, lower income, not being partnered, and comorbidities. Poorer psychological trajectories were predicted by younger age, lower income, comorbidities, and receiving radical prostatectomy or brachytherapy. Better urinary, bowel, and sexual function were related to better global outcomes over time. Anxiety about prostate specific antigen testing was rare. Distinct trajectories exist for medium- to long-term QoL, life satisfaction, and psychological adjustment after prostate cancer; with age and socioeconomic deprivation playing a differential role in men's survivorship profile and the impact of functional status on outcomes increasing over time. These results reinforce the need for an appraisal of men's life course in addition to treatment side effects when planning survivorship care after cancer.


Learning the parts of objects by non-negative matrix factorization.
Is perception of the whole based on perception of its parts? There is psychological and physiological evidence for parts-based representations in the brain, and certain computational theories of object recognition rely on such representations. But little is known about how brains or computers might learn the parts of objects. Here we demonstrate an algorithm for non-negative matrix factorization that is able to learn parts of faces and semantic features of text. This is in contrast to other methods, such as principal components analysis and vector quantization, that learn holistic, not parts-based, representations. Non-negative matrix factorization is distinguished from the other methods by its use of non-negativity constraints. These constraints lead to a parts-based representation because they allow only additive, not subtractive, combinations. When non-negative matrix factorization is implemented as a neural network, parts-based representations emerge by virtue of two properties: the firing rates of neurons are never negative and synaptic strengths do not change sign.


Characterisation of MRSA strains isolated from patients in a hospital in Riyadh, Kingdom of Saudi Arabia.
Methicillin-resistant Staphylococcus aureus (MRSA) is spreading worldwide and poses a serious public health problem, being present in hospital settings and communities. However, from the Middle East and the Arabian Peninsula few molecular typing data on MRSA strains are currently available. In order to obtain data on the population structure of MRSA in Riyadh, Saudi Arabia, 107 clinical and environmental MRSA isolates were genotyped using a microarray-based assay. Five major MRSA strains from four clonal complexes were identified CC8/ST239-III (20.75%), PVL-positive as well as -negative CC22-IV (18.87% and 9.43%, respectively), PVL-positive CC30-IV (12.26%) and PVL-positive CC80-IV (17.92%). Minor strains, which accounted for less than 3% each, included CC1-IV/SCCfus, PVL-positive CC1/ST772-V, PVL-positive as well as- negative CC5-IV, CC5-IV/SCCfus, CC5-V, CC6-IV, CC45-IV, PVL-negative CC80-IV, PVL-positive CC88-IV, CC97-V and a CC9/ST834-MRSA strain. Typing of MRSA strains from Riyadh revealed a high diversity of clonal complexes. The prevalence of the genes encoding the Panton-Valentine leukocidin was surprisingly high (54.21%), and a significant rate of resistance markers was detected also in strains considered as community-associated.


Human genetic determinants of dengue virus susceptibility.
Dengue virus (DENV) is an emerging mosquito-borne pathogen that produces significant morbidity worldwide resulting in an estimated 50-100 million infections annually. DENV causes a spectrum of illness ranging from inapparent infection to life-threatening hemorrhagic fever and shock. The varied DENV disease outcome is determined by complex interactions between immunopathologic, viral, and human genetic factors. This review summarizes these interactions with a focus on human genetic determinants of DENV susceptibility, including human leukocyte antigens, blood type, and single nucleotide polymorphisms in immune response genes that have been associated with DENV disease. We also discuss other factors related to DENV outcome including viral genetic determinants, age, ethnicity, and nutritional status as they relate to DENV susceptibility. We emphasize the need for functional genetics studies to complement association-based data and we call for controlled study designs and standard clinical DENV disease definitions that will strengthen conclusions based on human genetic DENV studies.


Expectations for nursing care in newborn units in Kenya: moving from implicit to explicit standards.
Neonatal mortality currently accounts for 45% of all child mortality in Kenya, standing at 22 per 1000 live births. Access to basic but high quality inpatient neonatal services for small and sick newborns will be key in reducing neonatal mortality. Neonatal inpatient care is reliant on nursing care, yet explicit nursing standards for such care do not currently exist in Kenya. We reviewed the Nursing Council of Kenya 'Manual of Clinical Procedures' to identify tasks relevant for the care of inpatient neonates. An expert advisory group comprising major stakeholders, policy-makers, trainers, and frontline health-workers was invited to a workshop with the purpose of defining tasks for which nurses are responsible and the minimum standard with which these tasks should be delivered to inpatient neonates in Kenyan hospitals. Despite differences in opinions at the beginning of the process, consensus was reached on the minimum standards of neonatal nursing. The key outcome was a comprehensive list and grouping of neonatal nursing task and the minimum frequency with which these tasks should be performed. Second, a simple categorisation of neonatal patients based on care needs was agreed. In addition, acceptable forms of task sharing with other cadres and the patient's family for the neonatal nursing tasks were agreed and described. The process was found to be acceptable to policy-makers and practitioners, who recognised the value of standards in neonatal nursing to improve the quality of neonatal inpatient care. Such standards could form the basis for audit and quality evaluation.


Determination of the differential mode delay of a multimode fiber using Fourierdomain intermodal interference analysis.
We present a novel differential mode delay (DMD) measurement method for a multimode optical fiber (MMF) based on Fourier-domain lowcoherence interferometry (fLCI) for the first time. An optical spectrum analyzer and a mode scrambler are used to obtain the intermodal interference signal in spectral domain after light passes an MMF. The MMF is used as a common path interferometer by itself without using any reference arm in an interferometer. Instead of using an offset launching technique, we present an effective method to obtain all available intermodal interference signals at a single shot by using a mode scrambler. The measured results using the proposed method are compared with those obtained using a conventional time-domain DMD measurement method.


Effect of ventilation improvement during a tuberculosis outbreak in underventilated university buildings.
The role of ventilation in preventing tuberculosis (TB) transmission has been widely proposed in infection control guidance. However, conclusive evidence is lacking. Modeling suggested the threshold of ventilation rate to reduce effective reproductive ratio (ratio between new secondary infectious cases and source cases) of TB to below 1 is corresponding to a carbon dioxide (CO2 ) level of 1000 parts per million (ppm). Here, we measured the effect of improving ventilation rate on a TB outbreak involving 27 TB cases and 1665 contacts in underventilated university buildings. Ventilation engineering decreased the maximum CO2 levels from 3204 ± 50 ppm to 591-603 ppm. Thereafter, the secondary attack rate of new contacts in university dropped to zero (mean follow-up duration: 5.9 years). Exposure to source TB cases under CO2 >1000 ppm indoor environment was a significant risk factor for contacts to become new infectious TB cases (P < .001). After adjusting for effects of contact investigation and latent TB infection treatment, improving ventilation rate to levels with CO2 <1000 ppm was independently associated with a 97% decrease (95% CI: 50%-99.9%) in the incidence of TB among contacts. These results show that maintaining adequate indoor ventilation could be a highly effective strategy for controlling TB outbreaks.


Parallel dual-color fluorescence cross-correlation spectroscopy using diffractive optical elements.
Dual-color cross-correlation spectroscopy allows the detection and quantification of labeled biomolecules at ultra-low concentrations, whereby the sensitivity of the assay correlates with the measurement time. We now describe a parallel multifocal dual-color spectroscopic configuration employing multiple avalanche photodiodes and hardware correlators. Cross-correlation curves are obtained from several dual-color excitation foci simultaneously. Multifocal dual-color excitation is achieved by splitting each of two laser beams (488 and 633 nm) into four sub-beams with the help of two 2x2 fan-out diffractive optical elements (DOEs), and subsequent superposition of the two sets of four foci. The fluorescence emission from double-labeled biomolecules is detected by two 2x2 fiber arrays.


Nutrient density of beverages in relation to climate impact.
The food chain contributes to a substantial part of greenhouse gas (GHG) emissions and growing evidence points to the urgent need to reduce GHGs emissions worldwide. Among suggestions were proposals to alter food consumption patterns by replacing animal foods with more plant-based foods. However, the nutritional dimensions of changing consumption patterns to lower GHG emissions still remains relatively unexplored. This study is the first to estimate the composite nutrient density, expressed as percentage of Nordic Nutrition Recommendations (NNR) for 21 essential nutrients, in relation to cost in GHG emissions of the production from a life cycle perspective, expressed in grams of CO(2)-equivalents, using an index called the Nutrient Density to Climate Impact (NDCI) index. The NDCI index was calculated for milk, soft drink, orange juice, beer, wine, bottled carbonated water, soy drink, and oat drink. Due to low-nutrient density, the NDCI index was 0 for carbonated water, soft drink, and beer and below 0.1 for red wine and oat drink. The NDCI index was similar for orange juice (0.28) and soy drink (0.25). Due to a very high-nutrient density, the NDCI index for milk was substantially higher (0.54) than for the other beverages. Future discussion on how changes in food consumption patterns might help avert climate change need to take both GHG emission and nutrient density of foods and beverages into account.


An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp.
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors1. One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown2. Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress3. However, Tas1 does not synthesize (p)ppGpp; instead, it pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 molecules per minute. Consequently, the delivery of Tas1 into competitor cells drives rapid accumulation of (p)ppApp, depletion of ATP, and widespread dysregulation of essential metabolic pathways, thereby resulting in target cell death. Our findings reveal a previously undescribed mechanism for interbacterial antagonism and demonstrate a physiological role for the metabolite (p)ppApp in bacteria.


Universal sequence replication, reversible polymerization and early functional biopolymers: a model for the initiation of prebiotic sequence evolution.
Many models for the origin of life have focused on understanding how evolution can drive the refinement of a preexisting enzyme, such as the evolution of efficient replicase activity. Here we present a model for what was, arguably, an even earlier stage of chemical evolution, when polymer sequence diversity was generated and sustained before, and during, the onset of functional selection. The model includes regular environmental cycles (e.g. hydration-dehydration cycles) that drive polymers between times of replication and functional activity, which coincide with times of different monomer and polymer diffusivity. Template-directed replication of informational polymers, which takes place during the dehydration stage of each cycle, is considered to be sequence-independent. New sequences are generated by spontaneous polymer formation, and all sequences compete for a finite monomer resource that is recycled via reversible polymerization. Kinetic Monte Carlo simulations demonstrate that this proposed prebiotic scenario provides a robust mechanism for the exploration of sequence space. Introduction of a polymer sequence with monomer synthetase activity illustrates that functional sequences can become established in a preexisting pool of otherwise non-functional sequences. Functional selection does not dominate system dynamics and sequence diversity remains high, permitting the emergence and spread of more than one functional sequence. It is also observed that polymers spontaneously form clusters in simulations where polymers diffuse more slowly than monomers, a feature that is reminiscent of a previous proposal that the earliest stages of life could have been defined by the collective evolution of a system-wide cooperation of polymer aggregates. Overall, the results presented demonstrate the merits of considering plausible prebiotic polymer chemistries and environments that would have allowed for the rapid turnover of monomer resources and for regularly varying monomer/polymer diffusivities.


Platelet interactions with fibronectin: divalent cation-independent platelet adhesion to the gelatin-binding domain of fibronectin.
Divalent cation-dependent platelet adhesion to fibronectin (FN) is mediated by the integrin receptors alpha 5 beta 1 (GP Ic-IIa) and alpha IIb beta 3 (GP IIb-IIIa), which recognize the RGD (Arg-Gly-Asp) sequence in the cell-binding domain. However, FN can also support divalent cation-independent platelet adhesion. To determine which domain of FN mediates divalent cation-independent adhesion, proteolysis with thermolysin and affinity chromatography were used to isolate the cell-binding, gelatin-binding, and heparin-binding domains of FN. Unactivated and thrombin-activated platelets adhered to intact FN and the 45-Kd gelatin-binding domain in the presence of either Ca2+ or EDTA. Platelet spreading was mediated only by the 105-Kd cell-binding domain and required divalent cations. The heparin-binding domains did not support platelet adhesion. Reduction of intrachain disulfide bonds or removal of carbohydrate side chains on the gelatin-binding domain did not alter the ability to support platelet adhesion. Divalent cation-independent adhesion to the 45-Kd gelatin-binding domain was not inhibited by RGDS (Arg-Gly-Asp-Ser) synthetic peptides or monoclonal antibodies (MoAbs) directed against known platelet receptors. We conclude that platelets can adhere but not spread on the gelatin-binding domain of FN by a novel divalent cation-independent mechanism.


Rank clocks and plant community dynamics.
Summarizing complex temporal dynamics in communities is difficult to achieve in a way that yields an intuitive picture of change. Rank clocks and rank abundance statistics provide a graphical and analytical framework for displaying and quantifying community dynamics. We used rank clocks, in which the rank order abundance for each species is plotted over time in temporal clockwise direction, to display temporal changes in species abundances and richness. We used mean rank shift and proportional species persistence to quantify changes in community structure in long-term data sets from fertilized and control plots in a late successional old field, frequently and infrequently burned tallgrass prairie, and Chihuahuan desert grassland and shrubland communities. Rank clocks showed that relatively constant species richness masks considerable temporal dynamics in relative species abundances. In the old field, fertilized plots initially experienced high mean rank shifts that stabilized rapidly below that of unfertilized plots. Rank shifts were higher in infrequently burned vs. annually burned tallgrass prairie and in desert grassland compared to shrubland vegetation. Proportional persistence showed that arid grasslands were more dynamic than mesic grasslands. We conclude that rank clocks and rank abundance statistics provide important insights into community dynamics that are often hidden by traditional univariate approaches.


Effects of Educational Interventions for Chronic Airway Disease on Primary Care.
Education has been known to essential for management of chronic airway diseases. However the real benefits remain unclear. We evaluated the effectiveness of an organized educational intervention for chronic airway diseases directed at primary care physicians and patients. The intervention was a 1-month education program of three visits, during which subjects were taught about their disease, an action plan in acute exacerbation and inhaler technique. Asthma control tests (ACT) for asthma and, chronic obstructive pulmonary disease (COPD) assessment tests (CAT) for COPD subjects were compared before and after education as an index of quality of life. Educational effectiveness was also measured associated with improvement of their knowledge for chronic airway disease itself, proper use of inhaler technique, and satisfaction of the subjects and clinicians before and after education. Among the 285 participants, 60.7% (n = 173) were men and the mean age was 62.2 ± 14.7. ACT for asthma and CAT in COPD patients were significantly improved by 49.7% (n = 79) and 51.2% (n = 65) more than MCID respectively after education (P < 0.05). In all individual items, knowledge about their disease, inhaler use and satisfaction of the patients and clinicians were also improved after education (P < 0.05). This study demonstrates the well-organized education program for primary care physicians and patients is a crucial process for management of chronic airway diseases.


High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness.
Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a perturbation observed in inflammatory states, tumor angiogenesis, atherosclerosis, and both sepsis and acute lung injury. Therefore, agents that enhance EC barrier integrity have important therapeutic implications. We observed that binding of high-molecular-weight hyaluronan (HMW-HA) to its cognate receptor CD44 within caveolin-enriched microdomains (CEM) enhances human pulmonary EC barrier function. Immunocytochemical analysis indicated that HMW-HA promotes redistribution of a significant population of CEM to areas of cell-cell contact. Quantitative proteomic analysis of CEM isolated from human EC demonstrated HMW-HA-mediated recruitment of cytoskeletal regulatory proteins (annexin A2, protein S100-A10, and filamin A/B). Inhibition of CEM formation [caveolin-1 small interfering RNA (siRNA) and cholesterol depletion] or silencing (siRNA) of CD44, annexin A2, protein S100-A10, or filamin A/B expression abolished HMW-HA-induced actin cytoskeletal reorganization and EC barrier enhancement. To confirm our in vitro results in an in vivo model of inflammatory lung injury with vascular hyperpermeability, we observed that the protective effects of HMW-HA on LPS-induced pulmonary vascular leakiness were blocked in caveolin-1 knockout mice. Furthermore, targeted inhibition of CD44 expression in the mouse pulmonary vasculature significantly reduced HMW-HA-mediated protection from LPS-induced hyperpermeability. These data suggest that HMW-HA, via CD44-mediated CEM signaling events, represents a potentially useful therapeutic agent for syndromes of increased vascular permeability.


Studies of ApoD-/- and ApoD-/-ApoE-/- mice uncover the APOD significance for retinal metabolism, function, and status of chorioretinal blood vessels.
Apolipoprotein D (APOD) is an atypical apolipoprotein with unknown significance for retinal structure and function. Conversely, apolipoprotein E (APOE) is a typical apolipoprotein with established roles in retinal cholesterol transport. Herein, we immunolocalized APOD to the photoreceptor inner segments and conducted ophthalmic characterizations of ApoD-/- and ApoD-/-ApoE-/- mice. ApoD-/- mice had normal levels of retinal sterols but changes in the chorioretinal blood vessels and impaired retinal function. The whole-body glucose disposal was impaired in this genotype but the retinal glucose metabolism was unchanged. ApoD-/-ApoE-/- mice had altered sterol profile in the retina but apparently normal chorioretinal vasculature and function. The whole-body glucose disposal and retinal glucose utilization were enhanced in this genotype. OB-Rb, both leptin and APOD receptor, was found to be expressed in the photoreceptor inner segments and was at increased abundance in the ApoD-/- and ApoD-/-ApoE-/- retinas. Retinal levels of Glut4 and Cd36, the glucose transporter and scavenger receptor, respectively, were increased as well, thus linking APOD to retinal glucose and fatty acid metabolism and suggesting the APOD-OB-Rb-GLUT4/CD36 axis. In vivo isotopic labeling, transmission electron microscopy, and retinal proteomics provided additional insights into the mechanism underlying the retinal phenotypes of ApoD-/- and ApoD-/-ApoE-/- mice. Collectively, our data suggest that the APOD roles in the retina are context specific and could determine retinal glucose fluxes into different pathways. APOD and APOE do not play redundant, complementary or opposing roles in the retina, rather their interplay is more complex and reflects retinal responses elicited by lack of these apolipoproteins.


Harmonized Outcome Measures for Use in Non-Small Cell Lung Cancer Patient Registries and Clinical Practice.
Lung cancer is the leading cause of cancer-related death in the United States and globally, and many questions exist about treatment options. Harmonizing data across registries and other data collection efforts would yield a robust data infrastructure to help address many research questions. The purpose of this project was to develop a minimum set of patient and clinician relevant harmonized outcome measures that can be collected in non-small cell lung cancer (NSCLC) patient registries and clinical practice. Seventeen lung cancer registries and related efforts were identified and invited to submit outcome measures. Representatives from medical specialty societies, government agencies, health systems, health information technology groups, patient advocacy organizations, and industry formed a stakeholder panel to categorize the measures and harmonize definitions using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework (OMF). The panel reviewed 66 outcome measures and identified a minimum set of 8 broadly relevant measures in the OMF categories of patient survival, clinical response, events of interest, and resource utilization. The panel harmonized definitions for the 8 measures through in-person and virtual meetings. The panel did not reach consensus on 1 specific validated instrument for capturing patient-reported outcomes. The minimum set of harmonized outcome measures is broadly relevant to clinicians and patients and feasible to capture across NSCLC disease stages and treatment pathways. A pilot test of these measures would be useful to document the burden and value of the measures for research and in clinical practice. By collecting the harmonized measures consistently, registries and other data collection systems could contribute to the development research infrastructure and learning health systems to support new research and improve patient outcomes.


Semi-supervised learning of the electronic health record for phenotype stratification.
Patient interactions with health care providers result in entries to electronic health records (EHRs). EHRs were built for clinical and billing purposes but contain many data points about an individual. Mining these records provides opportunities to extract electronic phenotypes, which can be paired with genetic data to identify genes underlying common human diseases. This task remains challenging: high quality phenotyping is costly and requires physician review; many fields in the records are sparsely filled; and our definitions of diseases are continuing to improve over time. Here we develop and evaluate a semi-supervised learning method for EHR phenotype extraction using denoising autoencoders for phenotype stratification. By combining denoising autoencoders with random forests we find classification improvements across multiple simulation models and improved survival prediction in ALS clinical trial data. This is particularly evident in cases where only a small number of patients have high quality phenotypes, a common scenario in EHR-based research. Denoising autoencoders perform dimensionality reduction enabling visualization and clustering for the discovery of new subtypes of disease. This method represents a promising approach to clarify disease subtypes and improve genotype-phenotype association studies that leverage EHRs.


Latissimus Dorsi Tendon Rupture.
Isolated injury to the latissimus dorsi is rare. Partial tendon tears may be successfully treated nonsurgically. Complete tendon ruptures require surgical repair. Tendon repair can be approached either through an anterior deltopectoral incision with a secondary small posterior axillary incision or through a long posterior axillary incision. Suture anchors can be used to repair the latissimus dorsi to the humeral attachment. Although the literature is limited to single-patient case series, most patients have returned to full athletic activity after surgical repair.


RETRACTED: Recent advances in cardiac regeneration: Stem cell, biomaterial and growth factors.
Myocardial infarction has been reported to be responsible for about 7.3 million deaths each year globally. Present treatments for myocardial infarction have been more palliative rather than curative. Over the past few years, stem cells have demonstrated its potency in regenerating damaged cardiac tissue, especially after myocardial infarction. However, limited short half-life of the protein and cell therapy and low transplanted cell survival rate as demonstrated via several clinical trials have lead to development of more potent and novel delivery systems like biomaterial delivery system and the use of various growth factors. In this review, we will be enumerating and discussing the recent advances in cardiac regeneration with focus on stem cell, biomaterial and growth factors.


Prediction of total green tea antioxidant capacity from chromatograms by multivariate modeling.
In this paper, a fast strategy for determining the total antioxidant capacity of Chinese green tea extracts is developed. This strategy includes the use of experimental techniques, such as fast high-performance liquid chromatography (HPLC) on monolithic columns and a spectrophotometric approach to determine the total antioxidant capacity of the extracts. To extract the chemically relevant information from the obtained data, chemometrical approaches are used. Among them there are correlation optimized warping (COW) to align the chromatograms, robust principal component analysis (robust PCA) to detect outliers, and partial least squares (PLS) and uninformative variable elimination partial least squares (UVE-PLS) to construct a reliable multivariate regression model to predict the total antioxidant capacity from the fast chromatograms.


Additively manufactured functionally graded biodegradable porous zinc.
Topological design provides additively manufactured (AM) biodegradable porous metallic biomaterials with a unique opportunity to adjust their biodegradation behavior and mechanical properties, thereby satisfying the requirements for ideal bone substitutes. However, no information is available yet concerning the effect of topological design on the performance of AM porous zinc (Zn) that outperforms Mg and Fe in biodegradation behavior. Here, we studied one functionally graded and two uniform AM porous Zn designs with diamond unit cell. Cylindrical specimens were fabricated from pure Zn powder by using a powder bed fusion technique, followed by a comprehensive study on their static and dynamic biodegradation behaviors, mechanical properties, permeability, and biocompatibility. Topological design, indeed, affected the biodegradation behavior of the specimens, as evidenced by 150% variations in biodegradation rate between the three different designs. After in vitro dynamic immersion for 28 days, the AM porous Zn had weight losses of 7-12%, relying on the topological design. The degradation rates satisfied the desired biodegradation time of 1-2 years for bone substitution. The mechanical properties of the biodegraded specimens of all the groups maintained within the range of those of cancellous bone. As opposed to the trends observed for other biodegradable porous metals, after 28 days of in vitro biodegradation, the yield strengths of the specimens of all the groups (σy = 7-14 MPa) increased consistently, as compared to those of the as-built specimens (σy = 4-11 MPa). Moreover, AM porous Zn showed excellent biocompatibility, given that the cellular activities in none of the groups differed from the Ti controls for up to 72 h. Using topological design of AM porous Zn for controlling its mechanical properties and degradation behavior is thus clearly promising, thereby rendering flexibility to the material to meet a variety of clinical requirements.


Science communication. Response to Comment on "Quantifying long-term scientific impact".
Wang, Mei, and Hicks claim that they observed large mean prediction errors when using our model. We find that their claims are a simple consequence of overfitting, which can be avoided by standard regularization methods. Here, we show that our model provides an effective means to identify papers that may be subject to overfitting, and the model, with or without prior treatment, outperforms the proposed naïve approach.


Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta-Analysis.
Neuromodulation is a treatment option for people suffering from painful diabetic neuropathy (PDN) unresponsive to conventional pharmacotherapy. We systematically examined the pain outcomes of patients with PDN receiving any type of invasive neuromodulation for treatment of neuropathic pain. MEDLINE and Embase were searched through 10 January 2020, without language restriction. All study types were included. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences. RCTs of tonic spinal cord stimulation (t-SCS) showed greater pain improvement than best medical therapy at six months (intention-to-treat: 38/100, 95% CI: 29-47). By per-protocol analysis, case series of t-SCS and dorsal root ganglion stimulation (DRGS) showed improvement by 56 (95% CI: 39-73) and 55 (22-87), respectively, at 12 months. For t-SCS, the rate of failing a therapeutic stimulation trial was 16%, the risk of infection was 4%, and the rate of lead problems requiring surgery to resolve was 4% per year of follow-up. High-frequency SCS and burst SCS both showed efficacy, with few patients studied. Efficacious, lasting and safe surgical pain management options are available to diabetic patients suffering from PDN. Tonic-SCS is the established standard of treatment; however, other SCS paradigms and DRGS are emerging as promising treatments offering comparable pain benefits, but with few cases published to date. Randomized controlled trials are ongoing to assess their relative merits.


Influence of occlusal scheme on the pressure distribution under a complete denture.
The purpose of this study was to estimate which occlusion offers the best conditions of pressure distribution on the supporting structure under a complete denture when crushing food. Simulated maxillary and mandibular complete dentures with three different posterior occlusal schemes--fully balanced occlusion, lingualized occlusion, and monoplane occlusion--were fabricated. Eight pressure transducers were placed in the basal surface of a mandibular denture. The pressure distribution on the mandibular edentulous mouth model with 1.5-mm-thick artificial tissue under a complete denture was recorded when crushing three different foods: soft food (kamaboko), peanuts, and carrot. The mean pressure values at each measurement point and the force required for each test were compared using one-way analysis of variance with P < or = 0.05 representing statistical significance. The required force for crushing a soft food or carrot in the left molar region in monoplane occlusion was significantly larger than that required in fully balanced occlusion or lingualized occlusion. In crushing soft food, fully balanced occlusion showed significantly higher pressure values on the working side than in monoplane occlusion or lingualized occlusion. In crushing the carrot, the pressure values in fully balanced occlusion and in lingualized occlusion were significantly lower than those in monoplane occlusion. These results demonstrate that with fully balanced occlusion and lingualized occlusion a large occlusal force is not needed for crushing hard food, and the stress to the supporting tissues is smaller than with monoplane occlusion.


Reexamining the Phosphorus-Protein Dilemma: Does Phosphorus Restriction Compromise Protein Status?
Dietary phosphorus restriction is recommended to help control hyperphosphatemia in hemodialysis patients, but many high-phosphorus foods are important sources of protein. In this review, we examine whether restricting dietary phosphorus compromises protein status in hemodialysis patients. Although dietary phosphorus and protein are highly correlated, phosphorus intakes can range up to 600 mg/day for a given energy and protein intake level. Furthermore, the collinearity of phosphorus and protein may be biased because the phosphorus burden of food depends on: (1) the presence of phosphate additives, (2) food preparation method, and (3) bioavailability of phosphorus, which are often unaccounted for in nutrition assessments. Ultimately, we argue that clinically relevant reductions in phosphorus intake can be made without limiting protein intake by avoiding phosphate additives in processed foods, using wet cooking methods such as boiling, and if needed, substituting high-phosphorus foods for nutritionally equivalent foods that are lower in bioavailable phosphorus.


Accounting for linguistic acculturation, coping, antisociality and depressive affect in the gender role-alcohol use relationship in Mexican American adolescents: a moderated mediation model for boys and girls.
Prior studies have established that gender roles are predictive of substance use for Mexican and Mexican American adolescents, both living in the U.S. and in Mexico. Objectives: The moderating effects of gender and acculturation and the mediating effects of antisociality, depressive affect, and adaptive and avoidant coping on the gender role-alcohol use relationship were examined in a sample of Mexican American adolescents. Secondary data analyses were conducted on a sample of 955 (450 boys, 505 girls) Mexican American 7th and 8th grade adolescents participating in a school-based substance use intervention. For boys, path analyses yielded significant direct paths from aggressive masculinity to alcohol use. Bootstrapped mediation tests also yielded significant indirect paths through antisociality from assertive masculinity, affective femininity, aggressive masculinity, and the interaction of linguistic acculturation by affective femininity to alcohol use. For girls, the relationship between aggressive masculinity with alcohol use and the negative relationship of affective femininity with alcohol use were also mediated by adaptive coping, which is predictive of decreased substance use. The present analyses confirm the importance of gender roles, functional mediators, and their interaction with acculturation in predicting substance use in Mexican American adolescents, with implications for the design of interventions to reduce substance use within the Mexican American community.


Reward learning in normal and mutant Drosophila.
Hungry fruit flies can be trained by exposing them to two chemical odorants, one paired with the opportunity to feed on 1 M sucrose. On later testing, when given a choice between odorants the flies migrate specifically toward the sucrose-paired odor. This appetitively reinforced learning by the flies is similar in strength and character to previously demonstrated negatively reinforced learning, but it differs in several properties. Both memory consolidation and memory decay proceed relatively slowly after training with sucrose reward. Consolidation of learned information into anesthesia-resistant long-term memory requires about 100 min after training with sucrose compared to about 30 min after training with electric shock. Memory in wild-type flies persists for 24 hr after training with sucrose compared to 4-6 hr after training with electric shock. Memory in amnesiac mutants appears to be similarly lengthened, from 1 hr to 6 hr, by substituting sucrose reward for shock punishment. Two other mutants, dunce and rutabaga, which were isolated because they failed to learn the shock-avoidance task, learn normally in response to sucrose reward but forget rapidly afterward. One mutant, turnip, does not learn in either paradigm. Reward and punishment can be combined in olfactory discrimination training by pairing one odor to sucrose and the other to electric shock. In this situation, the expression of learning is approximately the sum of that obtained by using either reinforcement alone. After such training, memory decays at two distinct rates, each characteristic of one type of reinforcement.


Regional differences in the occurrence of understorey species reflect nitrogen deposition in Swedish forests.
Possible links between the occurrence of Vaccinium myrtillus, V. vitis-idaea and Deschampsia flexuosa and rates of nitrogen deposition were investigated in 557 coniferous forest stands. In areas with high N-deposition, V. myrtillus was less frequent, less abundant and more susceptible to the leaf pathogen Valdensia heterodoxa than in areas with lower levels of N-deposition. The occurrence of V. vitis-idaea was also strongly negatively correlated with increasing N-deposition, but no such trend was found for D. flexuosa. In regions with high N-deposition, V. myrtillus was more common in stands dominated by Scots pine than in stands dominated by Norway spruce. This was not the case in regions with lower levels of N-deposition. The patterns observed accord with results from N-addition experiments that demonstrate significant effects on vegetation, caused by N-deposition. The data suggest that even low rates of N-deposition may decrease the abundance of the most dominant species in coniferous forest ground flora.


Cutaneous tuberculous gummas in a patient with polymyositis.
Metastatic tuberculous abscesses or cutaneous tuberculous gummas occur mostly by reactivation of ancient cutaneous foci and is triggered mainly by pharmacological immunosuppression, diabetes mellitus, alcoholism or acquired immunodeficiency syndrome. The present case report refers to a 33-year-old male patient with polymyositis and a previous diagnosis of treated pulmonary tuberculosis. He presented cutaneous abscesses and fever months after the tuberculosis regimen. The patient was diagnosed as metastatic tuberculous abscesses associated with immunosuppression as result of polymyositis treatment.


Thermal Recycling of Brominated Flame Retardants with Fe2O3.
Plastics containing brominated flame retardants (BFRs) constitute the major fraction of nonmetallic content in e-waste. Co-pyrolysis of BFRs with hematite (Fe2O3) represents a viable option for the thermal recycling of BFRs. Consensus of experimental findings confirms the excellent bromine fixation ability of Fe2O3 and the subsequent formation of iron bromides. This contribution provides a comprehensive mechanistic account of the primary reactions between a cluster model of Fe2O3 and major bromine-bearing products from the decomposition of tetrabromobisphenol A (TBBA), the most commonly deployed BFR. We estimate the thermo-kinetic parameters for interactions of Fe2O3 with HBr, brominated alkanes and alkenes, bromobenzene, and bromophenol. Dissociative addition of HBr at a Fe-O bond proceeds through a trivial barrier of 8.2 kcal/mol with fitted parameters in the Arrhenius equation of k(T) = 7.96 × 10(11) exp(-6400/RT) s(-1). The facile and irreversible nature for HBr addition to Fe2O3 accords with the experimentally reported 90% reduction in HBr emission when Fe2O3 interacts with TBBA pyrolysates. A detailed kinetic analysis indicates that, transformation of Fe2O3 into iron bromides and oxybromides occurs via successive addition of HBr to Fe(Br)-O(H) entities. Elimination of a water molecule proceeds through an intramolecular H transfer. A direct elimination one-step mechanism operates in the dehydrohalogenation of bromoethane into ethene over Fe2O3. Dissociative decomposition and direct elimination channels assume comparable reaction rates in formation of acetylene from vinyl bromide. Results from this study provide an atomic-based insight into a promising thermal recycling route of e-waste.


BMP and FGF regulate the development of EGF-responsive neural progenitor cells.
Temporal changes in progenitor cell responses to extrinsic signals play an important role in development, but little is known about the mechanisms that determine how these changes occur. In the rodent CNS, expression of epidermal growth factor receptors (EGFRs) increases during embryonic development, conferring mitotic responsiveness to EGF among multipotent stem cells. Here we show that cell-cell signaling controls this change. Whereas EGF-responsive stem cells develop on schedule in explant and aggregate cultures of embryonic cortex, co-culture with younger cortical cells delays their development. Exogenous BMP4 mimics the effect of younger cells, reversibly inhibiting changes in EGFR expression and responsiveness. Moreover, blocking endogenous BMP receptors in progenitors with a virus transducing dnBMPR1B accelerates changes in EGFR signaling. This involves a non-cell-autonomous mechanism, suggesting that BMP negatively regulates signal(s) that promote the development of EGF-responsive stem cells. FGF2 is a good candidate for such a signal, as we find that it antagonizes the inhibitory effects of younger cortical cells and exogenous BMP4. These findings suggest that a balance between antagonistic extrinsic signals regulates temporal changes in an intrinsic property of neural progenitor cells.


Clear water radiances for atmospheric correction of coastal zone color scanner imagery.
The possibility that the inherent sea surface spectral radiance of clear water can be computed in the green, yellow, and red regions of the spectrum solely from a knowledge of the solar zenith angle is developed in detail. This concept is tested with experimental data, and the results indicate that the normalized inherent sea surface spectral radiance is constant to within ~10% for Morel's Case 1 waters as long as the phytoplankton pigment concentration does not exceed 0.25 mg/m(3). In the same conditions the radiance at 670 nm is <0.012 mW/cm(2) microm sr. A scheme to implement this clear water radiance concept for atmospheric correction of CZCS imagery is presented.


Effects of hsp90 binding inhibitors on sGC-mediated vascular relaxation.
Vascular soluble guanylate cyclase (sGC) exists in multimeric complexes with endothelial nitric oxide (NO) synthase (eNOS) and heat shock protein 90 (hsp90). Whereas disruption of hsp90-eNOS complexes clearly attenuates eNOS-dependent vascular relaxation, the contribution of sGC-hsp90 complexes to eNOS- or NO donor-dependent relaxations remains unclear. Isolated rat thoracic aortic rings were preincubated with structurally diverse hsp90 binding inhibitors, radicicol (RA) or geldanamycin (GA), or vehicle for 0.5, 1, or 15 h. Preconstricted vessels were exposed to ACh, 8-bromo-cGMP (8-BrcGMP), forskolin, or one of three NO donors: nitroglycerin (NTG), sodium nitroprusside, or spermine NONOate (SNN). Both RA and GA inhibited endothelium-dependent relaxations dose dependently. Indomethacin or the antioxidant tiron did not affect the inhibition of ACh-induced relaxations by GA. Long-term (15 h) exposure to RA inhibited all NO donor-induced relaxations; however, GA inhibited SNN-induced relaxation only. The effects of GA and RA appeared to be selective because 15-h treatment with either agent did not affect forskolin-induced relaxations and only slightly decreased 8-BrcGMP-induced relaxations. Similarly to their effects on NO-donor-induced relaxation, 15-h exposure to RA, but not to GA, decreased hsp90-bound sGC protein expression and NTG-stimulated cGMP formation in aortic rings, whereas RA more than GA reduced SNN-stimulated cGMP formation. We conclude that RA, much more so than GA, selectively inhibits sGC-dependent relaxations of aortic rings by reducing sGC expression, disrupting sGC-hsp90 complex formation and decreasing cGMP formation. These studies suggest that hsp90 regulates both eNOS- and sGC-dependent relaxations.


Risk Assessment of Drug-Induced Long QT Syndrome for Some COVID-19 Repurposed Drugs.
The risk-benefit ratio associated with the use of repurposed drugs to treat severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-related infectious coronavirus disease 2019 (COVID-19) is complicated because benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID-19. A risk assessment of drug-induced long QT syndrome (LQTS) associated with COVID-19 repurposed drugs was performed and compared with 23 well-known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (IKr ) encoded by the human ether-a-go-go gene (hERG), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID-19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.


As time passes by: Observed motion-speed and psychological time during video playback.
Research shows that psychological time (i.e., the subjective experience and assessment of the passage of time) is malleable and that the central nervous system re-calibrates temporal information in accordance with situational factors so that psychological time flows slower or faster. Observed motion-speed (e.g., the visual perception of a rolling ball) is an important situational factor which influences the production of time estimates. The present study examines previous findings showing that observed slow and fast motion-speed during video playback respectively results in over- and underproductions of intervals of time. Here, we investigated through three separate experiments: a) the main effect of observed motion-speed during video playback on a time production task and b) the interactive effect of the frame rate (frames per second; fps) and motion-speed during video playback on a time production task. No main effect of video playback-speed or interactive effect between video playback-speed and frame rate was found on time production.


Protons, osmolytes, and fitness of internal milieu for protein function.
The composition of the intracellular milieu shows striking similarities among widely different species. Only certain values of intracellular pH, values that generally reflect alphastat regulation, and only narrow ranges of inorganic ion concentrations are found in the cytoplasm of the cells of most animals, plants, and microorganisms. In water-stressed organisms only a few types of low-molecular-weight organic molecules (osmolytes) are accumulated. These highly conserved characteristics of the intracellular fluids reflect the need to maintain critical features of macromolecules within narrow ranges optimal for life. For proteins these features include maintaining adequate rates of catalysis, a high level of regulatory responsiveness, and a precise balance between stability and lability of structure (tertiary conformation, subunit assembly, and multiprotein complexes). The optimal values for these functional and structural features of proteins often lie near the midrange of possible values for these properties, and only under specific conditions of intracellular pH, ionic strength, and osmolyte composition are these optimal midrange values conserved. In dormant cells the departure of solution conditions from values that are optimal for protein function and structure may be instrumental in reducing or shutting down metabolic functions. Seen from a broad evolutionary perspective, the evolution of the intracellular milieu is an important complement to macromolecular evolution. In certain instances appropriate modifications of the internal milieu may reduce the need for adaptive amino acid replacements in proteins.


Impact of newly diagnosed breast cancer on quality of life among Chinese women.
Being diagnosed with breast cancer is a very stressful event that has a profound impact on multiple aspects of a patient's daily life. Little is known about the quality of life (QOL) of Chinese women with newly diagnosed breast cancer. The authors evaluated QOL in 2,236 Chinese women with newly diagnosed breast cancer who were recruited into the Shanghai Breast Cancer Survival Study between April 1, 2002 and March 31, 2004. Patients' QOL was assessed after cancer diagnosis (median time 6.4 months; range 3.6-11.1 months) by using the General Quality of Life Inventory. Multiple linear regression models were used to analyze the associations of QOL outcomes with medical and socio-demographic factors. Patients showed significantly worse overall QOL and perceived health status than healthy women, reflected mainly by lower QOL scores in physical and psychological well-being domains. Completion of radiotherapy, ever use of tamoxifen, being underweight, having an increased number of chronic diseases, and low household income were significantly associated with lower overall QOL scores after adjusting for other factors. Age at diagnosis was inversely associated with physical well-being, positively associated with material well-being, and had minimal influence on overall QOL. Stage of disease, chemotherapy, and education were only associated with certain domains, but had no influence on overall QOL. Estrogen receptor/progesterone receptor status and type of surgery or immunotherapy did not appear to be associated with QOL. The findings of the present study provide important information on QOL and their correlates among Chinese women with newly diagnosed breast cancer and are helpful in developing treatment strategies accordingly.


Depression and competence to refuse psychiatric treatment.
Individuals with major depression may benefit from psychiatric treatment, yet they may refuse such treatment, sometimes because of their depression. Hence the question is raised whether such individuals are competent to refuse psychiatric treatment. The standard notion of competence to consent to treatment, which refers to expression of choice, understanding of medical information, appreciation of the personal relevance of this information, and logical reasoning, may be insufficient to address this question. This is so because major depression may not impair these four abilities while it may disrupt coherence of personal preferences by changing them. Such change may be evaluated by comparing the treatment preferences of the individual during the depression to his or her treatment preferences during normal periods. If these preferences are consistent, they should be respected. If they are not consistent, or past treatment preferences that were arrived at competently cannot be established, treatment refusal may have to be overridden or ignored so as to alleviate the depression and then determine the competent treatment decision of the individual. Further study of the relation between depression and competence to refuse or consent to psychiatric treatment is required.