Will Americans Get Vaccinated? Predicting COVID-19 Vaccine Uptake Rates Under Contingent Scenarios.
Amid a pandemic, vaccines represent a promising solution for mitigating public health and economic crises, and an improved understanding of individuals' vaccination intentions is crucial to design optimal immunization campaigns. This study predicts uptake rates for different COVID-19 vaccine specifications and identifies personal characteristics that moderate an individual's responsiveness to vaccine attributes. We developed an online survey with contingent specifications of a COVID-19 vaccine, varying in effectiveness, risks of side effects, duration of immunity, and out-of-pocket cost. Using population-averaged logit models, we estimated vaccine uptake rates that account for uncertainty, heterogeneity across respondents, and interactions between vaccine and personal characteristics. We obtained 3047 completed surveys. The highest uptake rate for an annual vaccine, 62%, is predicted when vaccine effectiveness is 80% to 90%, side effects are minimal, and the vaccine is provided at zero cost, with decreases seen in the uptake rate for less effective vaccines, for example, 50% for 50% to 60% effectiveness. Moreover, we found that Americans' response to vaccine effectiveness depends on their self-reported concern, that is, concerned respondents report a higher willingness to get vaccinated. Our findings also indicate that COVID-19 vaccine uptake rates decrease with vaccine cost and that responsiveness to vaccine cost is moderated by income. Although providing the COVID-19 vaccine at zero cost will motivate many individuals to get vaccinated, a policy focused exclusively on vaccine cost may not be enough to reach herd immunity thresholds. Although those concerned with COVID-19 will participate, further evidence is needed on how to incentivize participation among the unconcerned (43%) to prevent further pandemic spread.


Tip Streaming of a Lipid-Stabilized Double Emulsion Generated in a Microfluidic Channel.
Water/oil/water (w/o/w) double emulsions (DEs) are multicompartment structures which can be used in many technological applications and in fundamental studies as models of cell like microreactors or templates for other materials. Herein, we study the flow dynamics of water/oil/water double emulsions generated in a microfluidic device and stabilized with the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). We show that by varying the concentration of lipids in the oil phase (chloroform) or by modulating the viscosity of the aqueous continuous phase, the double emulsions under flow exhibit a rich dynamic behavior. An initial deformation of the double emulsions is followed by tube extraction at the rear end, relative to the flow direction, resulting in pinch off at the tube extremity by which small aqueous compartments are released. These compartments are phospholipid vesicles as deduced from fluorescence experiments. The overall process can thus be of help to shed light on the mechanical aspects of phenomena such as the budding and fusion in cell membranes.


Antiretroviral Drug Use and HIV Drug Resistance Among Young Women in Rural South Africa: HPTN 068.
Antiretroviral (ARV) drugs are used for HIV treatment and prevention. We analyzed ARV drug use and HIV drug resistance in a cohort of young women in rural South Africa enrolled in the HIV Prevention Trials Network (HPTN) 068 study, which evaluated the use of a cash transfer conditional on school attendance to reduce HIV incidence. ARV drug testing was performed using plasma samples from 2526 young women. This included 2526 enrollment samples (80 HIV-infected and 2446 HIV-uninfected) and 162 seroconversion samples (first HIV-positive study visit). Testing was performed using a qualitative assay that detects 20 ARV drugs from 5 drug classes. HIV drug resistance testing was performed with the ViroSeq HIV-1 Genotyping System for samples that had HIV viral loads ≥400 copies per milliliter. At enrollment, ARV drugs were detected in 10 (12.5%) of 80 HIV-infected young women. None of 2446 HIV-uninfected young women had ARV drugs detected at enrollment. ARV drugs were also detected in 16 (9.9%) of 162 seroconverters. At enrollment, 9 (13.4%) of 67 young women with genotyping results had HIV drug resistance; resistance was also detected in 9 (6.9%) of 131 seroconverters with genotyping results. Most of the HIV-infected young women in this cohort from rural South Africa were not taking ARV drugs, suggesting they were unaware of their HIV status or were not in care. HIV drug resistance was detected in young women with both prevalent and new HIV infection.


Proprietary tomato extract improves metabolic response to high-fat meal in healthy normal weight subjects.
Low-density lipoprotein (LDL) oxidation is a risk factor for atherosclerosis. Lycopene and tomato-based products have been described as potent inhibitors of LDL oxidation. To evaluate the effect of a 2-week supplementation with a carotenoid-rich tomato extract (CRTE) standardized for a 1:1 ratio of lycopene and phytosterols, on post-prandial LDL oxidation after a high-fat meal. In a randomized, double-blind, parallel-groups, placebo-controlled study, 146 healthy normal weight individuals were randomly assigned to a daily dose of CRTE standardized for tomato phytonutrients or placebo during 2 weeks. Oxidized LDL (OxLDL), glucose, insulin, and triglyceride (TG) responses were measured for 8 h after ingestion of a high-fat meal before and at the end of intervention. Plasma lycopene, phytofluene, and phytoene were increased throughout the study period in the CRTE group compared to placebo. CRTE ingestion significantly improved changes in OxLDL response to high-fat meal compared to placebo after 2 weeks (p<0.0001). Changes observed in glucose, insulin, and TG responses were not statistically significant after 2 weeks of supplementation, although together they may suggest a trend of favorable effect on metabolic outcomes after a high-fat meal. Two-week supplementation with CRTE increased carotenoids levels in plasma and improved oxidized LDL response to a high-fat meal in healthy normal weight individuals.


[Methods of correction of humoral and cellular immunity in patients with burns and erosive-ulcerative lesions of the gastrointestinal tract].
The levels of immunoglobulins G, IgA, M and T-rosette-forming lymphocytes were determined in parallel in 137 patients with burns. The endoscopic examination has revealed acute erosive-ulcerous lesions of the gastrointestinal tract in 48 of the patients. Interrelationship between the degree of morphological changes in the gastrointestinal tract, level of immunoglobulins G, IgA and amount of T-lymphocytes was established. It was found that against the background of complex therapy Levamisole, antioxidants, hyperbaric oxygenation facilitated most rapid recovery of the immunological status in burned patients, prevented the development of acute ulceration of the gastrointestinal tract and are considered as curative measures in their development.


Mutations in RPGR and RP2 account for 15% of males with simplex retinal degenerative disease.
To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region). This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration.


The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism.
Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed. The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S-13C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs. jQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software project, we hope it will attract additions from the community and grow with the rapidly changing field of metabolic engineering.


Ligand Profiling to Characterize Different Polymorphic Forms of α-Synuclein Aggregates.
The presence of amyloid fibrils is a characteristic feature of many diseases, most famously neurodegenerative disease. The supramolecular structure of these fibrils appears to be disease-specific. Identifying the unique morphologies of amyloid fibrils could, therefore, form the basis of a diagnostic tool. Here we report a method to characterize the morphology of α-synuclein (αSyn) fibrils based on profiling multiple different ligand binding sites that are present on the surfaces of fibrils. By employing various competition binding assays, seven different types of binding sites were identified on four different morphologies of αSyn fibrils. Similar binding sites on different fibrils were shown to bind ligands with significantly different affinities. We combined this information to construct individual profiles for different αSyn fibrils based on the distribution of binding sites and ligand interactions. These results demonstrate that ligand-based profiling can be used as an analytical method to characterize fibril morphologies with operationally simple fluorescence binding assays.


Symptoms of anxiety and depression in lesbian couples treated with donated sperm: a descriptive study.
To investigate symptoms of anxiety and depression in lesbian couples undergoing assisted reproductive treatment (ART), and to study the relationship of demographic data, pregnancy outcome and future reproductive plans with symptoms of anxiety and depression. Descriptive, a part of the prospective longitudinal 'Swedish study on gamete donation'. All university clinics in Sweden performing gamete donation. A consecutive sample of 214 lesbian couples requesting assisted reproduction, 165 of whom participated. Participants individually completed three study-specific questionnaires and the Hospital Anxiety and Depression Scale (HADS): time point 1 (T1), at commencement of ART; time point 2 (T2), approximately 2 months after treatment; and time point 3 (T3), 2-5 years after first treatment. Anxiety and depression (HADS), pregnancy outcome and future reproductive plans. The vast majority of lesbian women undergoing assisted reproduction reported no symptoms of anxiety and depression at the three assessment points. A higher percentage of the treated women, compared with the partners, reported symptoms of anxiety at T2 (14% versus 5%, P = 0.011) and T3 (10% versus 4%, P = 0.018), as well as symptoms of depression at T2 (4% versus 0%, P = 0.03) and T3 (3% versus 0%, P = 0.035). The overall pregnancy outcome was high; almost three-quarters of lesbian couples gave birth 2-5 years after sperm donation treatments. Open-ended comments illustrated joy and satisfaction about family building. Lesbian women in Sweden reported good psychological health before and after treatment with donated sperm.


A review of cohort study design for cardiovascular nursing research.
Nursing research encompasses a wide array of study areas that often times follow specific groups of patients or patient types. The cohort study design is a useful method to study any group, especially to track outcomes or to evaluate exposure or risk factors. Several different cohort study designs can be applied to the general population or to specific subpopulations or groups, such as those with cardiovascular disease. Cohort designs provide a temporal view of groups and exposures that can uncover outcomes and exposures that may be difficult to separate out in smaller, traditional experiments. There are several types of cohort designs, each with their unique advantages. Cohort designs may be prospective or retrospective. Although most cohort designs are longitudinal, there are also cross-sectional types of studies that are useful. As with any type of research design, selection of the study participants and control groups must be made carefully. It is important for the variables to be clearly defined and measurable. The investigator must also be aware of potential biases and weaknesses associated with different cohort study designs and account for these problems when they arise. Reports from cohort studies should be presented clearly, addressing the potential confounding problems. This article explores the many types of cohort designs, with examples from cardiovascular disease research to demonstrate how nurses can use this design in their research.


Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors.
Placebo analgesia is mediated by both opioid and nonopioid mechanisms, but so far nothing is known about the nonopioid component. Here we show that the specific CB1 cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant or SR141716) blocks nonopioid placebo analgesic responses but has no effect on opioid placebo responses. These findings suggest that the endocannabinoid system has a pivotal role in placebo analgesia in some circumstances when the opioid system is not involved.


High Density Genetic Maps of Seashore Paspalum Using Genotyping-By-Sequencing and Their Relationship to The Sorghum Bicolor Genome.
As a step towards trait mapping in the halophyte seashore paspalum (Paspalum vaginatum Sw.), we developed an F1 mapping population from a cross between two genetically diverse and heterozygous accessions, 509022 and HI33. Progeny were genotyped using a genotyping-by-sequencing (GBS) approach and sequence reads were analyzed for single nucleotide polymorphisms (SNPs) using the UGbS-Flex pipeline. More markers were identified that segregated in the maternal parent (HA maps) compared to the paternal parent (AH maps), suggesting that 509022 had overall higher levels of heterozygosity than HI33. We also generated maps that consisted of markers that were heterozygous in both parents (HH maps). The AH, HA and HH maps each comprised more than 1000 markers. Markers formed 10 linkage groups, corresponding to the ten seashore paspalum chromosomes. Comparative analyses showed that each seashore paspalum chromosome was syntenic to and highly colinear with a single sorghum chromosome. Four inversions were identified, two of which were sorghum-specific while the other two were likely specific to seashore paspalum. These high-density maps are the first available genetic maps for seashore paspalum. The maps will provide a valuable tool for plant breeders and others in the Paspalum community to identify traits of interest, including salt tolerance.


Serological evidence of vector and parasite exposure in Southern Ghana: the dynamics of malaria transmission intensity.
Seroepidemiology provides robust estimates for tracking malaria transmission when intensity is low and useful when there is no baseline entomological data. Serological evidence of exposure to malaria vectors and parasite contribute to our understanding of the risk of pathogen transmission, and facilitates implementation of targeted interventions. Ab to Anopheles gambiae salivary peptide (gSG6-P1) and merozoite surface protein one (MSP-1(19)) reflect human exposure to malaria vectors and parasites. This study estimated malaria transmission dynamics using serological evidence of vector and parasite exposure in southern Ghana. Total IgG responses to both antigens in an age stratified cohort (<5, 5-14, >14) were measured from South-eastern Ghana. 295 randomly selected sera were analyzed from archived samples belonging to a cohort study that were followed at 3 consecutive survey months (n = 885); February, May and August 2009. Temporal variations in seroprevalence of both antigens as well as differences between the age-stratified cohorts were determined by χ (2) test with p < 0.05 statistically significant. Non-parametric repeated ANOVA - Friedman's test was used to test differences in antibody levels. Seroprevalence data were fitted to reversible catalytic model to estimate sero-conversion rates. Whereas parasite prevalence was generally low 2.4%, 2.7% and 2.4% with no apparent trends with season, seroprevalence to both gSG6-P1 and MSP1(19) were high (59%, 50.9%, 52.2%) and 57.6%, 52.3% and 43.6% in respective order from Feb. to August. Repeated measures ANOVA showed differences in median antibody levels across surveys with specific significant differences between February and May but not August by post hoc Dunn's multiple comparison tests for gSG6-P1. For MSP1(19), no differences were observed in antibody levels between February and May but a significant decline was observed from May to August. Seroconversion rates for gSG6-P1 increased by 1.5 folds from February to August and 3 folds for MSP1(19). Data suggests exposure to infectious bites may be declining whereas mosquito bites remains high. Sustained malaria control efforts and surveillance are needed to drive malaria further down and to prevent catastrophic rebound. Operational factors for scaling up have been discussed.


A novel assembly mechanism for the DNA polymerase III holoenzyme DnaX complex: association of deltadelta' with DnaX(4) forms DnaX(3)deltadelta'.
We have constructed a plasmid-borne artificial operon that expresses the six subunits of the DnaX complex of Escherichia coli DNA polymerase III holoenzyme: tau, gamma, delta, delta', chi and psi. Induction of this operon followed by assembly in vivo produced two taugamma mixed DnaX complexes with stoichiometries of tau(1)gamma(2)deltadelta'chipsi and tau(2)gamma(1)deltadelta'chipsi rather than the expected gamma(2)tau(2)deltadelta'chipsi. We observed the same heterogeneity when taugamma mixed DnaX complexes were reconstituted in vitro. Re-examination of homomeric DnaX tau and gamma complexes assembled either in vitro or in vivo also revealed a stoichiometry of DnaX(3)deltadelta'chipsi. Equilibrium sedimentation analysis showed that free DnaX is a tetramer in equilibrium with a free monomer. An assembly mechanism, in which the association of heterologous subunits with a homomeric complex alters the stoichiometry of the homomeric assembly, is without precedent. The significance of our findings to the architecture of the holoenzyme and the clamp-assembly apparatus of all other organisms is discussed.


Integration of hybridization-based markers (overgos) into physical maps for comparative and evolutionary explorations in the genus Oryza and in Sorghum.
With the completion of the genome sequence for rice (Oryza sativa L.), the focus of rice genomics research has shifted to the comparison of the rice genome with genomes of other species for gene cloning, breeding, and evolutionary studies. The genus Oryza includes 23 species that shared a common ancestor 8-10 million years ago making this an ideal model for investigations into the processes underlying domestication, as many of the Oryza species are still undergoing domestication. This study integrates high-throughput, hybridization-based markers with BAC end sequence and fingerprint data to construct physical maps of rice chromosome 1 orthologues in two wild Oryza species. Similar studies were undertaken in Sorghum bicolor, a species which diverged from cultivated rice 40-50 million years ago. Overgo markers, in conjunction with fingerprint and BAC end sequence data, were used to build sequence-ready BAC contigs for two wild Oryza species. The markers drove contig merges to construct physical maps syntenic to rice chromosome 1 in the wild species and provided evidence for at least one rearrangement on chromosome 1 of the O. sativa versus Oryza officinalis comparative map. When rice overgos were aligned to available S. bicolor sequence, 29% of the overgos aligned with three or fewer mismatches; of these, 41% gave positive hybridization signals. Overgo hybridization patterns supported colinearity of loci in regions of sorghum chromosome 3 and rice chromosome 1 and suggested that a possible genomic inversion occurred in this syntenic region in one of the two genomes after the divergence of S. bicolor and O. sativa. The results of this study emphasize the importance of identifying conserved sequences in the reference sequence when designing overgo probes in order for those probes to hybridize successfully in distantly related species. As interspecific markers, overgos can be used successfully to construct physical maps in species which diverged less than 8 million years ago, and can be used in a more limited fashion to examine colinearity among species which diverged as much as 40 million years ago. Additionally, overgos are able to provide evidence of genomic rearrangements in comparative physical mapping studies.


Molecules and fossils reveal punctuated diversification in Caribbean "faviid" corals.
Even with well-known sampling biases, the fossil record is key to understanding macro-evolutionary patterns. During the Miocene to Pleistocene in the Caribbean Sea, the fossil record of scleractinian corals shows a remarkable period of rapid diversification followed by massive extinction. Here we combine a time-calibrated molecular phylogeny based on three nuclear introns with an updated fossil stratigraphy to examine patterns of radiation and extinction in Caribbean corals within the traditional family Faviidae. Concatenated phylogenetic analysis showed most species of Caribbean faviids were monophyletic, with the exception of two Manicina species. The time-calibrated tree revealed the stem group originated around the closure of the Tethys Sea (17.0 Ma), while the genus Manicina diversified during the Late Miocene (8.20 Ma), when increased sedimentation and productivity may have favored free-living, heterotrophic species. Reef and shallow water specialists, represented by Diploria and Favia, originate at the beginning of the Pliocene (5 - 6 Ma) as the Isthmus of Panama shoaled and regional productivity declined. Later origination of the stem group than predicted from the fossil record corroborates the hypothesis of morphological convergence in Diploria and Favia genera. Our data support the rapid evolution of morphological and life-history traits among faviid corals that can be linked to Mio-Pliocene environmental changes.


Impact of windows and daylight exposure on overall health and sleep quality of office workers: a case-control pilot study.
This research examined the impact of daylight exposure on the health of office workers from the perspective of subjective well-being and sleep quality as well as actigraphy measures of light exposure, activity, and sleep-wake patterns. Participants (N = 49) included 27 workers working in windowless environments and 22 comparable workers in workplaces with significantly more daylight. Windowless environment is defined as one without any windows or one where workstations were far away from windows and without any exposure to daylight. Well-being of the office workers was measured by Short Form-36 (SF-36), while sleep quality was measured by Pittsburgh Sleep Quality Index (PSQI). In addition, a subset of participants (N = 21; 10 workers in windowless environments and 11 workers in workplaces with windows) had actigraphy recordings to measure light exposure, activity, and sleep-wake patterns. Workers in windowless environments reported poorer scores than their counterparts on two SF-36 dimensions--role limitation due to physical problems and vitality--as well as poorer overall sleep quality from the global PSQI score and the sleep disturbances component of the PSQI. Compared to the group without windows, workers with windows at the workplace had more light exposure during the workweek, a trend toward more physical activity, and longer sleep duration as measured by actigraphy. We suggest that architectural design of office environments should place more emphasis on sufficient daylight exposure of the workers in order to promote office workers' health and well-being.


Reproductive hormone influences on thermoregulation in women.
The present discussion reviews current knowledge regarding influences of the primary reproductive hormones on mechanisms of thermoregulatory control in women. The human body is remarkably capable of maintaining body temperature within a few tenths of a degree of normal (37°C) over a wide range of activity and environmental exposures; this regulation is accomplished via integration of central and peripheral thermal information at the preoptic area of the anterior hypothalamus (PO/AH). We describe both central and peripheral mechanisms involved in controlling thermoregulation in humans, and how these mechanisms are affected by sex and hormone exposure. Estrogens generally promote vasodilation, heat dissipation, and lower body temperature and progesterone or progestins generally have the opposite effect. Estrogens and progesterone/progestins can also interact with androgens; this is an important point because androgens in the body can increase in both older and younger women. The study of reproductive hormone (estrogens, progesterone, luteinizing, and follicle stimulating hormones) effects on body systems is challenging because of the complex and multifaceted influences of these hormones, both individually and in combination. Thus, a number of methods to alter hormone exposure are explained in this article. We conclude that men and women do not exhibit major quantitative differences in physiological thermoregulatory responses to exercise and/or body heating when factors such as fitness and body size are taken into account. However, female and male reproductive hormones have important influences that can significantly alter individual thermoregulatory responses at various points throughout the lifespan.


REV-ERBα ameliorates heart failure through transcription repression.
A cure for heart failure remains a major unmet clinical need, and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. The pathological remodeling of the myocardium has been associated with a stereotypical gene expression program, which had long been viewed as the consequence and not the driver of the disease until very recently. Despite the advance, there is no therapy available to reverse the already committed gene program. Here, we demonstrate that transcriptional repressor REV-ERB binds near driver transcription factors across the genome. Pharmacological activation of REV-ERB selectively suppresses aberrant pathologic gene expression and prevents cardiomyocyte hypertrophy. In vivo, REV-ERBα activation prevents development of cardiac hypertrophy, reduces fibrosis, and halts progression of advanced heart failure in mouse models. Thus, to our knowledge, modulation of gene networks by targeting REV-ERBα represents a novel approach to heart failure therapy.


A gender analysis of the study of pharmacotherapy of psychotic depression (STOP-PD): gender and age as predictors of response and treatment-associated changes in body mass index and metabolic measures.
Gender differences exist in psychiatric disorders; however, gender has not been well studied in psychotic depression. This analysis of the largest clinical trial in psychotic depression examined the effects of age and gender on clinical characteristics and predictors of treatment outcome and treatment-associated changes in body mass index (BMI) and metabolic measures. Secondary analyses were performed on data from 259 subjects with major depressive disorder with psychotic features (DSM-IV-TR) aged 18-93 years in the double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression (Study of Pharmacotherapy of Psychotic Depression). Sociodemographic factors, clinical characteristics, treatment outcome, and treatment-associated changes in BMI and metabolic measures were analyzed by gender and age. Subjects were enrolled from December 2002 to June 2007. Female gender was associated with divorced (χ(2)(1) = 5.3, P = .03) or widowed (χ(2)(1) = 8.1, P ≤ .01) marital status. Comorbid anxiety disorders were more common in women than in men (χ(2)(1) = 4.9, P = .03). Hallucinations (χ(2)(1) = 7.8, P = .005) and delusions with disorganization (t(257) = -2.10, P = .04) were significantly associated with female gender, as were higher cholesterol measures (χ(2)(1) = 7.15, P = .008). There were no significant interactions between treatment and gender in terms of change in BMI. Gender was not associated with treatment response. This study is the first analysis of gender and age as predictors of treatment outcome and treatment-associated changes in BMI and metabolic adverse effects in psychotic depression. Gender differences exist in patients with psychotic depression, most notably with regard to the presence of hallucinations. Female gender was associated with metabolic measures. Future studies with larger sample sizes may detect small gender differences in treatment outcome and treatment-associated changes in BMI and metabolic measures in psychotic depression. ClinicalTrials.gov identifier: NCT00056472.


The Yin and Yang of Nicotine: Harmful during Development, Beneficial in Adult Patient Populations.
Nicotine has remarkably diverse effects on the brain. Being the main active compound in tobacco, nicotine can aversively affect brain development. However, it has the ability to act positively by restoring attentional capabilities in smokers. Here, we focus on nicotine exposure during the prenatal and adolescent developmental periods and specifically, we will review the long-lasting effects of nicotine on attention, both in humans and animal models. We discuss the reciprocal relation of the beneficial effects of nicotine, improving attention in smokers and in patients with neuropsychiatric diseases, such as schizophrenia and attention deficit/hyperactivity disorder, vs. nicotine-related attention deficits already caused during adolescence. Given the need for research on the mechanisms of nicotine's cognitive actions, we discuss some of the recent work performed in animals.


Energy Metabolism of the Osteoblast: Implications for Osteoporosis.
Osteoblasts, the bone-forming cells of the remodeling unit, are essential for growth and maintenance of the skeleton. Clinical disorders of substrate availability (e.g., diabetes mellitus, anorexia nervosa, and aging) cause osteoblast dysfunction, ultimately leading to skeletal fragility and osteoporotic fractures. Conversely, anabolic treatments for osteoporosis enhance the work of the osteoblast by altering osteoblast metabolism. Emerging evidence supports glycolysis as the major metabolic pathway to meet ATP demand during osteoblast differentiation. Glut1 and Glut3 are the principal transporters of glucose in osteoblasts, although Glut4 has also been implicated. Wnt signaling induces osteoblast differentiation and activates glycolysis through mammalian target of rapamycin, whereas parathyroid hormone stimulates glycolysis through induction of insulin-like growth factor-I. Glutamine is an alternate fuel source for osteogenesis via the tricarboxylic acid cycle, and fatty acids can be metabolized to generate ATP via oxidative phosphorylation although temporal specificity has not been established. More studies with new model systems are needed to fully understand how the osteoblast utilizes fuel substrates in health and disease and how that impacts metabolic bone diseases.


Screening and Brief Interventions for Illicit Drug Use and Alcohol Use in Methadone Maintained Opiate-Dependent Patients: Results of a Pilot Cluster Randomized Controlled Trial Feasibility Study.
The present study evaluated the effectiveness of a single clinician delivered brief intervention (BI) to reduce problem alcohol use and illicit substance use in an opiate-dependent methadone maintained cohort of patients attending for treatment. Four addiction treatment centers were randomly assigned to either treatment as usual (TAU; control group) or BI (intervention group). Clinicians screened patients using the alcohol, smoking, and substance involvement screening test (ASSIST) screening tool at baseline and again at three-month follow up. Fidelity checks were performed to ensure that training was delivered effectively and uniformly across all study sites. Feasibility of administering a BI within daily practice was assessed through intervention fidelity checks, patient satisfaction questionnaires and process evaluation. A total of 465 patients were screened (66% of the overall eligible population) with a total of 433 (93%) ASSIST positive cases. Randomization was effective, with no differences in the control versus the intervention arms at baseline for key demographic or clinical indicators including substance us. There was a statistically significant difference between global risk score for the intervention (x = 39.36, sd = 25.91) group and the control group (x = 45.27, SD = 27.52) at 3-month follow-up (t(341) = -2.07, p < .05). This trial provides the first evidence that a single clinician delivered BI can result in a reduction in substance use within a methadone maintained opiate-dependent cohort, and this effect is sustained at three month follow up.


Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway.
TGF-beta can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-beta while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bone-metastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.


Enhancing the application of effective malaria interventions in Africa through training.
Africa bears more than 90% of the entire global malaria disease burden. Surprisingly, even with the current renewed interest in malaria prevention and control and the enabling environment resulting from the Roll Back Malaria initiative and the political commitment made by the African Presidents at the Abuja Summit, there are still no significant initiatives for strengthening capacity for malaria control through training within the African continent itself. The Center for Enhancement of Effective Malaria Interventions (CEEMI) has been established in Dar es Salaam, Tanzania for results-oriented training. It is intended to provide the needed skills for identifying and solving malaria control problems and providing incentives to malaria control workers in their work performance. The intention is to produce implementers with leadership skills for planning and managing malaria control activities and who can use strategic thinking in improving their work performance. To sustain political commitment and support and to sensitize the community on malaria issues, the CEEMI, in collaboration with the Ministry of Health (National Malaria Control Program), the Institute of Journalism and Mass Communication of the University of Dar es Salaam, and the Commonwealth Broadcasting Association have already conducted malaria seminars for Tanzanian Members of Parliament and journalists from Kenya, Malawi, Tanzania, and Uganda. Additionally, a diploma course in health communication is being developed for journalists and for the same purpose. Also being developed is a training module for "Council Malaria Focal Person." This is aimed at complementing the Roll Back Malaria initiative to meet the Abuja targets of reducing morbidity and mortality due to malaria by 50% by 2010.


Abnormal brain processing in hepatic encephalopathy: evidence of cerebral reorganization?
Hepatic encephalopathy (HE) is a severe and frequent complication of liver cirrhosis characterized by abnormal cerebral function. Little is known about the underlying neural mechanisms in HE and human data are sparse. Electrophysiological methods such as evoked brain potentials after somatic stimuli can be combined with inverse modeling of the underlying brain activity. Thereby, information on neuronal dynamics and brain activity can be studied in vivo. The aim of this study was to investigate the sensory brain processing in patients with HE. Twelve patients with minimal or overt HE and 26 healthy volunteers were included in the study. Cerebral sensory processing was investigated as (i) an auditory reaction time task; (ii) visual and somatosensory evoked brain potentials, and (iii) reconstruction of the underlying brain activity. Somatosensory evoked potentials were reproducible (all P>0.05), whereas flash evoked potentials were not reproducible (all P<0.05). Compared with healthy volunteers, the patient group had a prolonged reaction time index (P=0.03) along with increasing prolongation of latencies of median nerve evoked potentials (P<0.03). Reconstruction of the underlying brain sources showed a lateral shift in source localization of the P45 (P<0.001) and N60 components (P=0.02). A correlation between the psychometric hepatic encephalopathy score and the dipole shift corresponding to the N60 (P=0.003) component was seen. HE patients have evidence of prolonged intracerebral nerve conduction, along with lateralization of brain activity following median nerve stimulation. This possibly represents cortical reorganization and may be important in our understanding of this condition.


Evidence that 5-hydroxytryptamine(7) receptors play a role in the mediation of afferent transmission within the nucleus tractus solitarius in anaesthetized rats.
Central 5-hydroxytryptamine (5-HT)-containing pathways utilizing 5-HT(7) receptors are known to be critical for the mediation of cardiovascular reflexes. The nucleus tractus solitarius (NTS) is a site involved in the integration of cardiovascular afferent information. The present experiments examined the involvement of the 5-HT(7) receptor in the processing of cardiovascular reflexes in the NTS. In anaesthetized rats extracellular recordings were made from 104 NTS neurones that were excited by electrical stimulation of the vagus nerve and/or activation of cardiopulmonary afferents. Drugs were applied ionophoretically in the vicinity of these neurones. The non-selective 5-HT(7) receptor agonist 5-carboxamidotryptamine maleate (5-CT) applied to 78 neurones increased the firing rate in 18 by 59% and decreased it in 38 neurones by 47%. Similarly, the 5-HT(1A) agonist 8-OH-DPAT applied to 20 neurones had an excitatory (8), inhibitory (7) or no effect (5) on the 20 neurones tested. In the presence of the 5-HT(7) antagonist SB 258719 the 5-CT excitation was attenuated. Furthermore, the excitatory response of NTS neurones evoked by electrical stimulation of the vagus nerve or activation of cardiopulmonary afferents with intra atrial phenylbiguanide was attenuated by SB 258719. The inhibitory action of 5-CT was unaffected by SB 258719 and the 5-HT(1A) antagonist WAY-100635. WAY-100635 failed to have any effect on 5-CT and vagal afferent-evoked excitations. Vagal afferent-evoked excitation of NTS neurones can be blocked by SB 258719, a selective 5-HT(7) antagonist. This observation further supports the involvement of 5-HT neurotransmission in NTS afferent processing.


Role of developmental transcription factors in white, brown and beige adipose tissues.
In this review we discuss the role of developmental transcription factors in adipose tissue biology with a focus on how these developmental genes may contribute to regional variation in adipose tissue distribution and function. Regional, depot-specific, differences in lipid handling and signalling (lipolysis, lipid storage and adipokine/lipokine signalling) are important determinants of metabolic health. At a cellular level, preadipocytes removed from their original depot and cultured in vitro retain depot-specific functional properties, implying that these are intrinsic to the cells and not a function of their environment in situ. High throughput screening has identified a number of developmental transcription factors involved in embryological development, including members of the Homeobox and T-Box gene families, that are strongly differentially expressed between regional white adipose tissue depots and also between brown and white adipose tissue. However, the significance of depot-specific developmental signatures remains unclear. Developmental transcription factors determine body patterning during embryogenesis. The divergent developmental origins of regional adipose tissue depots may explain their differing functional characteristics. There is evidence from human genetics that developmental genes determine adipose tissue distribution: in GWAS studies a number of developmental genes have been identified as being correlated with anthropometric measures of adiposity and fat distribution. Additionally, compelling functional studies have recently implicated developmental genes in both white adipogenesis and the so-called 'browning' of white adipose tissue. Understanding the genetic and developmental pathways in adipose tissue may help uncover novel ways to intervene with the function of adipose tissue in order to promote health.


Enhancing fieldworkers' performance management support in health research: an exploratory study on the views of field managers and fieldworkers from major research centres in Africa.
Fieldworkers are part of the system that promotes scientific and ethical standards in research, through data collection, consenting and supporting research, due to their insider cultural knowledge and fluency in local languages. The credibility and integrity of health research, therefore, rely on how fieldworkers adhere to institutional and research procedures and guidelines. This study mapped out existing practices in training, support and performance management of fieldworkers in Africa, described fieldworkers' and their managers' experiences, and lessons learnt. A consultative process, involving field managers from 15 international health research institutions, was used to identify appropriate ways of addressing the challenges fieldworkers face. In phase 1, we conducted 32 telephone interviews with 20 field managers and 12 senior fieldworkers from 18 major research centres in Africa, Medical Research Council-UK and the INDEPTH Network Secretariat. In phase 2, we held a 2.5-day workshop involving 25 delegates, including 18 field managers from the institutions that were involved in phase 1 and 7 additional stakeholders from the KEMRI Wellcome Trust Research Programme (KWTRP). An earlier report from phase 1 was published in BMC MedicalEthics in 2015. Data transcribed from the interviews and workshop proceedings were analysed thematically using NVivo V.10 software. Most institutions employed fieldworkers, usually with 12 years of formal education and residing within the geographical areas of research, to support studies. Although their roles were common, there were marked differences in the type of training, professional development schemes and fieldworkers support. Fieldworkers faced various challenges, with the potential to affect their ethical and scientific practices. Fieldworkers undertake vital tasks that promote data quality and ethical practice in research. There is a need for research institutions to develop a structured support system, provide fieldworkers with interpersonal skills training, and provide space for discussion, reflection and experience sharing to help fieldworkers tackle the practical and ethical challenges they face.


Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy.
Chromosomal aneuploidy, that is to say the gain or loss of chromosomes, is the most common abnormality in cancer. While certain aberrations, most commonly translocations, are known to be strongly associated with specific cancers and contribute to their formation, most aberrations appear to be non-specific and arbitrary, and do not have a clear effect. The understanding of chromosomal aneuploidy and its role in tumorigenesis is a fundamental open problem in cancer biology. We report on a systematic study of the characteristics of chromosomal aberrations in cancers, using over 15,000 karyotypes and 62 cancer classes in the Mitelman Database. Remarkably, we discovered a very high co-occurrence rate of chromosome gains with other chromosome gains, and of losses with losses. Gains and losses rarely show significant co-occurrence. This finding was consistent across cancer classes and was confirmed on an independent comparative genomic hybridization dataset of cancer samples. The results of our analysis are available for further investigation via an accompanying website. The broad generality and the intricate characteristics of the dichotomy of aneuploidy, ranging across numerous tumor classes, are revealed here rigorously for the first time using statistical analyses of large-scale datasets. Our finding suggests that aneuploid cancer cells may use extra chromosome gain or loss events to restore a balance in their altered protein ratios, needed for maintaining their cellular fitness.


Association of the sickle cell trait and the ABO blood group with clinical severity of malaria in southwest Nigeria.
In regions of high Plasmodium falciparum malaria endemicity, certain erythrocyte polymorphisms confer resistance to severe disease. In this study, we evaluate the role of the sickle cell trait (HbS) and ABO blood groups in the clinical manifestations of childhood malaria in Southwest Nigeria. The subjects comprised 3100 children (53% males, median age 39 months), including 1400 children with uncomplicated malaria, 1000 children with asymptomatic malaria and 700 with severe malaria. Haemoglobin (Hb) types were determined using electrophoresis and serum agglutination techniques were used to determine ABO blood groups. Blood group O was the commonest ABO blood group (47.7%) in the study population, the others were A (22.5%), B (25.2%) and AB (4.6%). The frequencies of the HbAS and HbAC were 14.4% and 5.8%, respectively. In regression models adjusting for age, gender, parasite density and blood group, HbAS was associated with a reduced risk of severe malaria OR=0.46 (CI(95%): 0.273-0.773). Among severe malaria subjects, HbAS was associated with significantly lower parasite densities. The protective effect of blood group O was demonstrated with a decreased risk of severe malaria OR=0.743 (CI(95%): 0.566-0.976) after adjusting for age, gender and parasite density and Hb genotype. Blood group B was associated with increased risk of severe malaria OR=1.638 (CI(95%): 1.128-2.380) after adjusting for age, gender, packed cell volume, parasite density and Hb genotype. We have confirmed from this large study of Nigerian children the major protective effective of the sickle cell heterozygous state against both cerebral malaria and severe malarial anaemia. We also show that the B blood group is associated with an increased risk of severe malaria. In conclusion, the sickle cell haemoglobin type and ABO groups modulate the risk of severe malaria in Nigerian children.


Wolves in sheep's clothing: SDO asymmetrically predicts perceived ethnic victimization among white and Latino students across three years.
Dominant groups have claimed to be the targets of discrimination on several historical occasions during violent intergroup conflict and genocide.The authors argue that perceptions of ethnic victimization among members of dominant groups express social dominance motives and thus may be recruited for the enforcement of group hierarchy. They examine the antecedents of perceived ethnic victimization among dominants, following 561 college students over 3 years from freshman year to graduation year. Using longitudinal, cross-lagged structural equation modeling, the authors show that social dominance orientation (SDO) positively predicts perceived ethnic victimization among Whites but not among Latinos, whereas victimization does not predict SDO over time. In contrast, ethnic identity and victimization reciprocally predicted each other longitudinally with equal strength among White and Latino students. SDO is not merely a reflection of contextualized social identity concerns but a psychological, relational motivation that undergirds intergroup attitudes across extended periods of time and interacts with the context of group dominance.


Oral and sublingual immunotherapy for food allergy.
IgE-mediated food allergy is a potentially life-threatening allergic disease with an increase in prevalence in developed countries over the past 15 years. Currently, there are no approved forms of therapy and the standard of care is dietary restriction and ready access to emergency medications, such as self-injectable epinephrine and antihistamines. Allergen-specific modalities of treatment currently being studied include oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). Both forms demonstrate the ability to desensitize patients to a variety of specific food allergens and show great promise. However, more research is needed to evaluate the safety and efficacy of OIT and SLIT prior to routine use in clinical practice.


A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer.
An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m(2) twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine. Mol Cancer Ther; 15(9); 2251-8. ©2016 AACR.


Smoking and harm-reduction efforts among postpartum women.
The authors present findings from a qualitative study on postpartum smoking among low-income women ( N = 44) who had been smokers at the onset of pregnancy. Interview data collected after delivery at Months 1, 3, and 6 postpartum are discussed to explore contextual factors contributing to smoking abstinence, relapse, and harm-reduction practices. By 6 months postpartum, 10 women (23%) had completely quit, 21 women (48%) had reduced their smoking by 50% of their prepregnancy levels, and 7 women (16%) had reduced their smoking by one third of their prepregnancy levels. Thus, the majority of the women were engaging in significant harm-reduction efforts despite being entrenched in high-risk smoking environments where they were provided with few messages to quit. Many mothers were concerned about their moral identity as a smoker and expressed concerns that their child might initiate smoking at an early age. Future programs targeting this population should acknowledge women's harm-reduction efforts in environments where smoking is normative.


Automated Urban Travel Interpretation: A Bottom-up Approach for Trajectory Segmentation.
Understanding travel behavior is critical for an effective urban planning as well as for enabling various context-aware service provisions to support mobility as a service (MaaS). Both applications rely on the sensor traces generated by travellers' smartphones. These traces can be used to interpret travel modes, both for generating automated travel diaries as well as for real-time travel mode detection. Current approaches segment a trajectory by certain criteria, e.g., drop in speed. However, these criteria are heuristic, and, thus, existing approaches are subjective and involve significant vagueness and uncertainty in activity transitions in space and time. Also, segmentation approaches are not suited for real time interpretation of open-ended segments, and cannot cope with the frequent gaps in the location traces. In order to address all these challenges a novel, state based bottom-up approach is proposed. This approach assumes a fixed atomic segment of a homogeneous state, instead of an event-based segment, and a progressive iteration until a new state is found. The research investigates how an atomic state-based approach can be developed in such a way that can work in real time, near-real time and offline mode and in different environmental conditions with their varying quality of sensor traces. The results show the proposed bottom-up model outperforms the existing event-based segmentation models in terms of adaptivity, flexibility, accuracy and richness in information delivery pertinent to automated travel behavior interpretation.


Establishment of hepatitis C virus RNA-replicating cell lines possessing ribavirin-resistant phenotype.
Ribavirin (RBV) is a potential partner of interferon-based therapy and recently approved therapy using direct acting antivirals for patients with chronic hepatitis C. However, the precise mechanisms underlying RBV action against hepatitis C virus (HCV) replication are not yet understood. To clarify this point, we attempted to develop RBV-resistant cells from RBV-sensitive HCV RNA-replicating cells. By repetitive RBV (100 μM) treatment (10 weeks) of 3.5-year-cultured OL8 cells, in which genome-length HCV RNA (O strain of genotype 1b) efficiently replicates, dozens of colonies that survived RBV treatment were obtained. These colonies were mixed together and further treated with high doses of RBV (up to 200 μM). By such RBV treatment, we successfully established 12 RBV-survived genome-length HCV RNA-replicating cell lines. Among them, three representative cell lines were characterized. HCV RNA replication in these cells resisted RBV significantly more than that in the parental OL8 cells. Genetic analysis of HCV found several common and conserved amino acid substitutions in HCV proteins among the three RBV-resistant cell species. Furthermore, using cDNA microarray and quantitative RT-PCR analyses, we identified 5 host genes whose expression levels were commonly altered by more than four-fold among these RBV-resistant cells compared with the parental cells. Moreover, to determine whether viral or host factor contributes to RBV resistance, we developed newly HCV RNA-replicating cells by introducing total RNAs isolated from RBV-sensitive parental cells or RBV-resistant cells into the HCV RNA-cured-parental or -RBV-resistant cells using an electroporation method, and evaluated the degrees of RBV resistance of these developed cells. Consequently, we found that RBV-resistant phenotype was conferred mainly by host factor and partially by viral factor. These newly established HCV RNA-replicating cell lines should become useful tools for further understanding the anti-HCV mechanisms of RBV.


A conceptual model of psychosomatic illness in children. Family organization and family therapy.
Linear and open systems (multiple feedback) models of psychosomatic illness in children are contrasted in terms of their implications for cause and treatment. An open systems family model is presented that describes three necessary (but not independently sufficient) conditions for the development and maintenance of severe psychosomatic problems in children: (1) a certain type of family organization that encourages somatization; (2) involvement of the child in parental conflict; and (3) physiological vulnerability. Predisposition for psychosomatic illness, symptom choice, and maintenance are discussed within this conceptual framework. We report on family therapy strategies based on this model and the results of family treatment with 48 cases of "brittle" diabetes, psychosomatic asthma, and anorexia nervosa.


Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves.
We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity. Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linköping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation. Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given grader's ordering of images with the group average to 0.86 to 0.90. Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies.


DNA Metabarcoding of Amazonian Ichthyoplankton Swarms.
Tropical rainforests harbor extraordinary biodiversity. The Amazon basin is thought to hold 30% of all river fish species in the world. Information about the ecology, reproduction, and recruitment of most species is still lacking, thus hampering fisheries management and successful conservation strategies. One of the key understudied issues in the study of population dynamics is recruitment. Fish larval ecology in tropical biomes is still in its infancy owing to identification difficulties. Molecular techniques are very promising tools for the identification of larvae at the species level. However, one of their limits is obtaining individual sequences with large samples of larvae. To facilitate this task, we developed a new method based on the massive parallel sequencing capability of next generation sequencing (NGS) coupled with hybridization capture. We focused on the mitochondrial marker cytochrome oxidase I (COI). The results obtained using the new method were compared with individual larval sequencing. We validated the ability of the method to identify Amazonian catfish larvae at the species level and to estimate the relative abundance of species in batches of larvae. Finally, we applied the method and provided evidence for strong temporal variation in reproductive activity of catfish species in the Ucayalí River in the Peruvian Amazon. This new time and cost effective method enables the acquisition of large datasets, paving the way for a finer understanding of reproductive dynamics and recruitment patterns of tropical fish species, with major implications for fisheries management and conservation.


X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
The ClC chloride channels catalyse the selective flow of Cl- ions across cell membranes, thereby regulating electrical excitation in skeletal muscle and the flow of salt and water across epithelial barriers. Genetic defects in ClC Cl- channels underlie several familial muscle and kidney diseases. Here we present the X-ray structures of two prokaryotic ClC Cl- channels from Salmonella enterica serovar typhimurium and Escherichia coli at 3.0 and 3.5 A, respectively. Both structures reveal two identical pores, each pore being formed by a separate subunit contained within a homodimeric membrane protein. Individual subunits are composed of two roughly repeated halves that span the membrane with opposite orientations. This antiparallel architecture defines a selectivity filter in which a Cl- ion is stabilized by electrostatic interactions with alpha-helix dipoles and by chemical coordination with nitrogen atoms and hydroxyl groups. These findings provide a structural basis for further understanding the function of ClC Cl- channels, and establish the physical and chemical basis of their anion selectivity.


Adsorption of methylamine on mackinawite (FES) surfaces: a density functional theory study.
We have used density functional theory calculations to investigate the interaction between methylamine (CH3NH2) and the dominant surfaces of mackinawite (FeS), where the surface and adsorption properties of mackinawite have been characterized using the DFT-D2 method of Grimme. Our calculations show that while the CH3NH2 molecule only interacts weakly with the most stable FeS(001), it adsorbs relatively strongly on the FeS(011) and FeS(100) surfaces releasing energies of 1.26 eV and 1.51 eV, respectively. Analysis of the nature of the bonding reveals that the CH3NH2 molecule interacts with the mackinawite surfaces through the lone-pair of electrons located on the N atom. The electron density built up in the bonding region between N and Fe is very much what one would expect of covalent type of bonding. We observe no significant adsorption-induced changes of the FeS surface structures, suggesting that amine capping agents would not distort the FeS nanoparticle surfaces required for active heterogeneous catalytic reactions. The vibrational frequencies and the infrared spectra of adsorbed methylamine have been calculated and assignments for vibrational modes are used to propose a kinetic model for the desorption process, yielding a simulated temperature programmed desorption with a relative desorption temperature of <140 K at the FeS(011) surface and <170 K at FeS(100) surface.


Infection control in design and construction work.
To clarify how infection control requirements are represented, communicated, and understood in work interactions through the medical facility construction project life cycle. To assist project participants with effective infection control management by highlighting the nature of such requirements and presenting recommendations to aid practice. A 4-year study regarding client requirement representation and use on National Health Service construction projects in the United Kingdom provided empirical evidence of infection control requirement communication and understanding through design and construction work interactions. An analysis of construction project resources (e.g., infection control regulations and room data sheets) was combined with semi-structured interviews with hospital client employees and design and construction professionals to provide valuable insights into the management of infection control issues. Infection control requirements are representationally indistinct but also omnipresent through all phases of the construction project life cycle: Failure to recognize their nature, relevance, and significance can result in delays, stoppages, and redesign work. Construction project resources (e.g., regulatory guidance and room data sheets) can mask or obscure the meaning of infection control issues. A preemptive identification of issues combined with knowledge sharing activities among project stakeholders can enable infection control requirements to be properly understood and addressed. Such initiatives should also reference existing infection control regulatory guidance and advice.


Biofilm-forming capacity, surface hydrophobicity and aggregation characteristics of Myroides odoratus isolated from South African Oreochromis mossambicus fish.
Although Myroides spp. are primarily isolated from clinical sources, they have also been isolated from freshwater fish, stainless steel weldment and catheter biofilms. The ability of these nonmotile isolates to adhere to surfaces and the role of hydrophobicity and autoaggregation were investigated. Adherence of Myroides odoratus isolates from tilapia was investigated using microtitre adherence assays under varying environmental conditions. Hydrophobicity, aggregation and coaggregation were measured quantitatively. Biofilm structures were investigated using flow cells and microscopy. Myroides odoratus isolates were strongly adherent in both nutrient-poor and -rich media at room temperature and nutrient-rich medium at 37 degrees C. Isolates appeared hydrophilic, while autoaggregation indices ranged from 7% to 24.8%. Statistically significant positive correlations were observed between biofilm formation and autoaggregation. Strong coaggregation interactions were observed with several Gram-positive organisms, as well as with Listeria spp. In flow cells, M. odoratus formed an overlying carpet, with knitted chains of L. monocytogenes cells situated underneath attached to the perspex flow cell surface. Myroides odoratus biofilm formation was influenced by temperature variation rather than altered nutrient levels. The association of Myroides spp. with Listeria spp. isolates suggests potential association in biofilm structures when these bacteria colonize biotic and/or abiotic surfaces.


The role of the arcuate and middle longitudinal fasciculi in speech perception in noise in adulthood.
In this article, we used High Angular Resolution Diffusion Imaging (HARDI) with advanced anatomically constrained particle filtering tractography to investigate the role of the arcuate fasciculus (AF) and the middle longitudinal fasciculus (MdLF) in speech perception in noise in younger and older adults. Fourteen young and 15 elderly adults completed a syllable discrimination task in the presence of broadband masking noise. Mediation analyses revealed few effects of age on white matter (WM) in these fascicles but broad effects of WM on speech perception, independently of age, especially in terms of sensitivity and criterion (response bias), after controlling for individual differences in hearing sensitivity and head size. Indirect (mediated) effects of age on speech perception through WM microstructure were also found, after controlling for individual differences in hearing sensitivity and head size, with AF microstructure related to sensitivity, response bias and phonological priming, and MdLF microstructure more strongly related to response bias. These findings suggest that pathways of the perisylvian region contribute to speech processing abilities, with relatively distinct contributions for the AF (sensitivity) and MdLF (response bias), indicative of a complex contribution of both phonological and cognitive processes to age-related speech perception decline. These results provide new and important insights into the roles of these pathways as well as the factors that may contribute to elderly speech perception deficits. They also highlight the need for a greater focus to be placed on studying the role of WM microstructure to understand cognitive aging.


Ecosystem functioning and maximum entropy production: a quantitative test of hypotheses.
The idea that entropy production puts a constraint on ecosystem functioning is quite popular in ecological thermodynamics. Yet, until now, such claims have received little quantitative verification. Here, we examine three 'entropy production' hypotheses that have been forwarded in the past. The first states that increased entropy production serves as a fingerprint of living systems. The other two hypotheses invoke stronger constraints. The state selection hypothesis states that when a system can attain multiple steady states, the stable state will show the highest entropy production rate. The gradient response principle requires that when the thermodynamic gradient increases, the system's new stable state should always be accompanied by a higher entropy production rate. We test these three hypotheses by applying them to a set of conventional food web models. Each time, we calculate the entropy production rate associated with the stable state of the ecosystem. This analysis shows that the first hypothesis holds for all the food webs tested: the living state shows always an increased entropy production over the abiotic state. In contrast, the state selection and gradient response hypotheses break down when the food web incorporates more than one trophic level, indicating that they are not generally valid.


Implementation of a patient blood management monitoring and feedback program significantly reduces transfusions and costs.
Patient blood management (PBM) measures have been shown to be effective in reducing transfusions while maintaining patient outcome. The issuance of transfusion guidelines is seen as being key to the success of PBM programs. As the introduction of guidelines alone did not visibly reduce transfusions in our center, a monitoring and feedback program was established. The aim of our study was to show the effectiveness of such measures in reducing transfusions and cost. We designed a prospective, interventional cohort study with a 3-year time frame (January 1, 2012 to December 31, 2014). In total, 101,794 patients aged 18 years or older were included. The PBM monitoring and feedback program was introduced on January 1, 2014, with the subsequent issuance of quarterly reporting. Within the first year of introduction, transfusion of all allogeneic blood products per 1000 patients was reduced by 27% (red blood cell units, -24%; platelet units, -25%; and fresh-frozen plasma units, -37%; all p < 0.001) leading to direct allogeneic blood product related savings of more than 2 million USD. The number of blood products transfused per case was significantly reduced from 9 ± 19 to 7 ± 14 (p < 0.001). With an odds ratio of 0.86 (95% confidence interval, 0.82-0.91), the introduction of our PBM monitoring and feedback program was a significant independent factor in the reduction of transfusion probability (p < 0.001). Our PBM monitoring and feedback program was highly efficacious in reducing the transfusion of allogeneic blood products and transfusion-related costs.


Life Beyond 65: Changing Spatial Patterns of Survival at Older Ages in the United States, 2000-2016.
To identify levels and trends in life expectancy at age 65 (e65) by geographic region and metropolitan status in the United States. Using county-level data on population and deaths from the Census and National Center for Health Statistics, we consider spatial inequality in e65 across 4 metropolitan types and 10 geographic regions from 2000 to 2016. We examine whether changes in e65 are driven by mortality developments in metro types or geographic regions, and compare spatial patterns in the United States to mortality trends in other Organization of Economic Cooperation and Development (OECD) countries. We use decomposition and regression methods to estimate the contributions of 10 causes of death to changes and inequalities in e65. Life expectancy at age 65 increased in all spatial units from 2000 to 2016. Areas with higher e65 in 2000 also experienced larger gains. Longevity increases were greatest in large metropolitan areas and coastal regions. Nonmetropolitan areas and the interior lagged far behind not only other parts of the United States but all OECD comparison countries. Metropolitan status was a better predictor of mortality changes than geographic region. Circulatory diseases and diseases associated with smoking were the principal sources of life expectancy gains and spatial differentiation in those gains. Larger gains in smoking-related mortality accounted for greater improvements among men than women. Even at advanced ages, large geographic disparities in life expectancy remain. And as mortality has declined, these disparities have widened. Public health efforts should pay special attention to identifying and ameliorating the sources of lagging life expectancy in nonmetropolitan regions.


Inflammation of the Pleural Cavity: A Review on Pathogenesis, Diagnosis and Implications in Tumor Pathophysiology.
Pleural effusions are a common respiratory condition with many etiologies. Nonmalignant etiologies explain most pleural effusions and despite being nonmalignant, they can be associated with poor survival; thus, it is important to understand their pathophysiology. Furthermore, diagnosing a benign pleural pathology always harbors the uncertainty of a false-negative diagnosis for physicians and pathologists, especially for the group of non-specific pleuritis. This review aims to present the role of the inflammation in the development of benign pleural effusions, with a special interest in their pathophysiology and their association with malignancy.


Endothelial cell specification in the somite is compromised in Pax3-positive progenitors of Foxc1/2 conditional mutants, with loss of forelimb myogenesis.
Pax3 and Foxc2 have been shown genetically to mutually repress each other in the mouse somite. Perturbation of this balance in multipotent cells of the dermomyotome influences cell fate; upregulation of Foxc2 favours a vascular fate, whereas higher levels of Pax3 lead to myogenesis. Foxc1 has overlapping functions with Foxc2. In Foxc1/2 double-mutant embryos, somitogenesis is severely affected, precluding analysis of somite derivatives. We have adopted a conditional approach whereby mutations in Foxc1 and Foxc2 genes were targeted to Pax3-expressing cells. Inclusion of a conditional reporter allele in the crosses made it possible to follow cells that had expressed Pax3. At the forelimb level, endothelial and myogenic cells migrate from adjacent somites into the limb bud. This population of endothelial cells is compromised in the double mutant, whereas excessive production of myogenic cells is observed in the trunk. However, strikingly, myogenic progenitors fail to enter the limbs, leading to the absence of skeletal muscle. Pax3-positive migratory myogenic progenitors, marked by expression of Lbx1, are specified in the somite at forelimb level, but endothelial progenitors are absent. The myogenic progenitors do not die, but differentiate prematurely adjacent to the somite. We conclude that the small proportion of somite-derived endothelial cells in the limb is required for the migration of myogenic limb progenitors.


Demography and Natural Selection Have Shaped Genetic Variation in the Widely Distributed Conifer Norway Spruce (Picea abies).
Under the neutral theory, species with larger effective population size are expected to harbor higher genetic diversity. However, across a wide variety of organisms, the range of genetic diversity is orders of magnitude more narrow than the range of effective population size. This observation has become known as Lewontin's paradox and although aspects of this phenomenon have been extensively studied, the underlying causes for the paradox remain unclear. Norway spruce (Picea abies) is a widely distributed conifer species across the northern hemisphere, and it consequently plays a major role in European forestry. Here, we use whole-genome resequencing data from 35 individuals to perform population genomic analyses in P. abies in an effort to understand what drives genome-wide patterns of variation in this species. Despite having a very wide geographic distribution and an corresponding enormous current population size, our analyses find that genetic diversity of P. abies is low across a number of populations (π = 0.0049 in Central-Europe, π = 0.0063 in Sweden-Norway, π = 0.0063 in Finland). To assess the reasons for the low levels of genetic diversity, we infer the demographic history of the species and find that it is characterized by several reoccurring bottlenecks with concomitant decreases in effective population size can, at least partly, provide an explanation for low polymorphism we observe in P. abies. Further analyses suggest that recurrent natural selection, both purifying and positive selection, can also contribute to the loss of genetic diversity in Norway spruce by reducing genetic diversity at linked sites. Finally, the overall low mutation rates seen in conifers can also help explain the low genetic diversity maintained in Norway spruce.


A polymer-based probe for specific discrimination of cysteine.
A novel optically active methacrylic polymer with an amide-linked acrylate appendage as a chemosensor was synthesized by atom transfer radical polymerization (ATRP) followed by post-modification through a bottom-up design. The sensing behavior of the polymeric probe to various α-amino acids has been investigated through fluorescence, absorption, circular dichroism (CD), and visual color changes at physiological pH. It was found that the sensor exhibits specificity for the fluorescent recognition of cysteine against other amino acids and thiols in a turn-on mode, being significantly more effective than the corresponding small molecule counterpart. The detection limit was estimated to be in the micromolar range. In addition, the use of this chiral polymer allows the selective discrimination of cysteine enantiomers based on either fluorescence or CD spectral responses. Interestingly, the cysteine assay could also be visualized by the naked eye in the presence of small amounts of ferric ions.


Compressive sensing with dispersion compensation on non-linear wavenumber sampled spectral domain optical coherence tomography.
We propose a novel compressive sensing (CS) method on spectral domain optical coherence tomography (SDOCT). By replacing the widely used uniform discrete Fourier transform (UDFT) matrix with a new sensing matrix which is a modification of the non-uniform discrete Fourier transform (NUDFT) matrix, it is shown that undersampled non-linear wavenumber spectral data can be used directly in the CS reconstruction. Thus k-space grid filling and k-linear mask calibration which were proposed to obtain linear wavenumber sampling from the non-linear wavenumber interferometric spectra in previous studies of CS in SDOCT (CS-SDOCT) are no longer needed. The NUDFT matrix is modified to promote the sparsity of reconstructed A-scans by making them symmetric while preserving the value of the desired half. In addition, we show that dispersion compensation can be implemented by multiplying the frequency-dependent correcting phase directly to the real spectra, eliminating the need for constructing complex component of the real spectra. This enables the incorporation of dispersion compensation into the CS reconstruction by adding the correcting term to the modified NUDFT matrix. With this new sensing matrix, A-scan with dispersion compensation can be reconstructed from undersampled non-linear wavenumber spectral data by CS reconstruction. Experimental results show that proposed method can achieve high quality imaging with dispersion compensation.


m(1)A and m(1)G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs.
The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G-C(+) (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result,N(1)-methyladenosine and N(1)-methylguanosine, which occur in DNA as a form of alkylation damage and in RNA as post-transcriptional modifications, have dramatically different consequences. Whereas they create G-C(+) and A-T Hoogsteen base pairs in duplex DNA, thereby maintaining the structural integrity of the double helix, they block base-pairing and induce local duplex melting in RNA. These observations provide a mechanism for disrupting RNA structure through post-transcriptional modifications. The different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help cells meet the opposing requirements of maintaining genome stability, on the one hand, and of dynamically modulating the structure of the epitranscriptome, on the other.


Sustained benefit of supportive intervention for depressive symptoms in caregivers of patients with Alzheimer's disease.
The long-term effect of counseling and support on symptoms of depression was examined in spouse-caregivers of patients with Alzheimer's disease. The participants were 406 spouse-caregivers of Alzheimer's disease patients who lived at home at baseline. The caregivers were randomly assigned to either a group receiving enhanced counseling and support treatment or a group receiving usual care (control group). Caregivers in the enhanced treatment group were provided with six sessions of individual and family counseling, agreed to join support groups 4 months after enrollment, and received ongoing ad hoc counseling. The Geriatric Depression Scale was administered at baseline and at regular follow-up intervals for as long as the caregiver participated in the study. After baseline differences were controlled for, caregivers in the enhanced treatment group had significantly fewer depressive symptoms after the intervention than did the control subjects. These effects were sustained for 3.1 years after baseline, similar across gender and patient severity level, and sustained after nursing home placement or death of the patient. Counseling and support lead to sustained benefits in reducing depressive symptoms in spouse-caregivers of Alzheimer's disease patients and should be widely available to provide effective, evidence-based intervention for family caregivers.


Transient ischemic attacks. Retrospective study of 150 cases of ischemic infarct in the territory of the middle cerebral artery.
Transient ischemic attacks (TIA) are episodes of abrupt beginning, consisting of subjective or objective neurological dysfunction of short duration, with complete recovery of neurological function in the course of 24 hours. With this definition, the authors carried out a retrospective study of 150 patients suffering from ischemic infarct in the brain in the territory of the middle cerebral artery. Thirty-eight percent of the patients had had TIAs before their cerebral infarct. The symptoms, in order of frequency, were motor, sensory deficits, alterations of speech and vision. Most of the patients had a definite cerebral infarct, occurring one month after the last TIA; the symptoms of both processes were remarkably similar. The authors studied the angiographic characteristics, pharmacological and toxic antecedents, and associated diseases in these patients. The study indicates that TIA may be the first manifestation of cerebral vascular disease.


Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles.
Extracellular vesicles (EVs) are small membrane-bound organelles naturally released from cells and potentially function as vehicles of intercellular communication. Cells release numerous sub-species of EVs, including exosomes and microvesicles, which are formed via distinct cellular pathways and molecular machineries and contain specific proteins, RNAs and lipids. Accumulating evidence indicates that the repertoire of molecules packaged into EVs is shaped by both the physiological state of the cell and the EV biogenesis pathway involved. Although these observations intimate that precisely regulated pathways sort molecules into EVs, the underlying molecular mechanisms that direct molecules for secretion remain poorly defined. Recently, with the advancement of mass spectrometry, next-generation sequencing techniques and molecular biology tools, several mechanisms contributing to EV cargo selection are beginning to be unraveled. This review examines strategies employed to reveal how specific proteins, RNAs and lipids are directed for secretion via EVs.


Does attention bias modification induce structural brain changes? A commentary on Abend et al. (2019).
The strength of research conclusions must follow from the strength of evidence. In this commentary I raise several issues with a recent paper "Brain structure changes induced by attention bias modification training" (Abend et al., 2019). I follow the paper's five highlights to discuss; the absence of discussion of negative ABM results, the low power of the study itself. Centrally, I raise the concern that the conclusions rest all their weight on a single statistically significant group x time interaction form brain-wide analysis. Most importantly, this test is not internally consistent following statcheck. The reported result requires checking, and potentially a correction that would shift the results entirely.


In vivo and in vitro Approaches Reveal Novel Insight Into the Ability of Epicardium-Derived Cells to Create Their Own Extracellular Environment.
Human epicardium-derived cells (hEPDCs) transplanted in the NOD-SCID mouse heart after myocardial infarction (MI) are known to improve cardiac function, most likely orchestrated by paracrine mechanisms that limit adverse remodeling. It is not yet known, however, if hEPDCs contribute to preservation of cardiac function via the secretion of matrix proteins and/or matrix proteases to reduce scar formation. This study describes the ability of hEPDCs to produce human collagen type I after transplantation into the infarct border zone, thereby creating their own extracellular environment. As the in vivo environment is too complex to investigate the mechanisms involved, we use an in vitro set-up, mimicking biophysical and biochemical cues from the myocardial tissue to unravel hEPDC-induced matrix remodeling. The in vivo contribution of hEPDCs to the cardiac extracellular matrix (ECM) was assessed in a historical dataset of the NOD-SCID murine model of experimentally induced MI and cell transplantation. Analysis showed that within 48 h after transplantation, hEPDCs produce human collagen type I. The build-up of the human collagen microenvironment was reversed within 6 weeks. To understand the hEPDCs response to the pathologic cardiac microenvironment, we studied the influence of cyclic straining and/or transforming growth beta (TGFβ) signaling in vitro. We revealed that 48 h of cyclic straining induced collagen type I production via the TGFβ/ALK5 signaling pathway. The in vitro approach enables further unraveling of the hEPDCs ability to secrete matrix proteins and matrix proteases and the potential to create and remodel the cardiac matrix in response to injury.


Determinants of spirometry use and accuracy of COPD diagnosis in primary care.
It is unclear if primary care physicians are following guidelines or using other patient characteristics and factors to determine when to perform spirometry in patients at risk for COPD. It is also unclear to what degree a diagnosis of COPD is accurately reflected by spirometry results. To examine characteristics associated with use of spirometry in primary care for patients with increased risk for COPD and to determine the accuracy of COPD diagnosis in patients with spirometry. Retrospective cohort study. A cohort that met the following criteria was identified: ≥35 years of age; ≥ 2 primary care visits in internal medicine clinic in 2007; at least one respiratory or smoking cessation medication, or diagnosis of COPD or shortness of breath or dyspnea in 2007. Medical records of all primary care physician visits prior to the time of inclusion in 2007 were reviewed. Data on patient demographics, co-morbidities, respiratory medication use, presence of symptoms, history of tobacco use, and pulmonary function tests were extracted. A total 1052 patients were identified. Dyspnea on exertion (Adjusted odds ratio (AOR) 1.52 [95% CI 1.06-2.18]) and chronic cough (AOR 1.71 [1.07-2.72]) were the only chronic symptoms associated with use of spirometry. Current (AOR 1.54 [0.99-2.40]) or past smoking (AOR 1.09 [0.72-1.65]) status were not associated with use of spirometry. Of the 159 patients with a diagnosis of COPD, 93 (58.5%) met GOLD criteria and 81(50.9%) met lower limit of normal (LLN) criteria for COPD. Clinicians use spirometry more often among patients with symptoms suggestive of COPD but not more often among patients with current or past tobacco use. For patients who had a spirometry and a diagnosis of COPD, primary care physicians were accurate in their diagnosis only half of the time.


Localization and identification of thrombin and plasminogen activator activities in model human thrombi by in situ zymography.
Human thrombi vary in their susceptibility to lysis and this is clinically important. Several potential contributory factors were examined in this study by using model thrombi, created under flow; these provide a robust, reproducible and easily-manipulated system. Here we identify the plasminogen activators (PA) active in model thrombi of known age and define the cellular and plasma contribution to activity in different areas. The cell-rich head of model thrombi had strong thrombin and PA activity, with coagulant activity also at the tail. Thrombin activity decreased as model thrombi were aged. PA activity in the thrombus head also decreased on ageing of thrombi but activity emerged around the thrombi, including the tail. Activity in the head of fresh model thrombi was primarily due to uPA, with some contribution from tPA. Experiments with thrombi prepared from platelet-rich plasma and added leucocytes showed that uPA activity at the head of fresh thrombi was derived from PMN. Older thrombi had tPA activity around the tail of the thrombus; this activity occurred in the absence of cells. This study highlights the importance of PMN-derived uPA activity in the lysis of fresh thrombi, with activity originating in the leucocyte-rich head. It also shows that thrombi are dynamic structures in which fibrin can be repeatedly laid down and lysed, observations that are relevant to therapeutic lysis and potential rethrombosis.


Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways.
The purpose of the present study was to elucidate the possible signal transduction pathway involved in the underlying mechanism of glucosamine (GLN)'s influence on the gene expression of matrix metalloproteinases (MMPs) in chondrocytes stimulated with IL-1beta. Using chondrosarcoma cells stimulated with IL-1beta, the effects of GLN on the mRNA and protein levels of MMP-3, the activation of JNK, ERK, p38, NF-kappaB, and AP-1, the nuclear translocation of NF-kappaB/Rel family members, and PI3-kinase/Akt activation were studied. GLN inhibited the expression and the synthesis of MMP-3 induced by IL-1beta, and that inhibition was mediated at the level of transcription involving both the NF-kappaB and AP-1 transcription factors. Translocation of NF-kappaB was reduced by GLN as a result of the inhibition of IkappaB degradation. A slightly synergistic effect on the activation of AP-1 induced by IL-1beta was shown in the presence of GLN. Among MAPK pathways involved in the transcriptional regulation of AP-1, phosphorylation of JNK and ERK was found to increase with the presence of GLN under IL-1beta treatment, while that for p38 decreased. It was also found that GLN alone, but also synergistically with IL-1beta, was able to activate the Akt pathway. The requirements of NF-kappaB translocation and p38 activity are indispensably involved in the induction of MMP-3 expression in chondrosarcoma cells stimulated by IL-1beta. Inhibition of the p38 pathway in the presence of GLN substantially explains the chondroprotective effect of GLN on chondrocytes that regulate COX-2 expression, PGE(2) synthesis, and NO expression and synthesis. The chondroprotective effect of GLN through the decrease in MMP-3 production and stimulation of proteoglycan synthesis may follow another potential signaling pathway of Akt.


The pathophysiology of heart failure: a tale of two old paradigms revisited.
Although our current appreciation of the detrimental role of neurohumoral activation in heart failure (HF) has been intellectually appealing and has led to neurohumoral antagonism that has reduced morbidity and mortality from HF, the persisting disability and death rates remain unacceptably high. In the search for novel strategies to improve on these outcomes, we must reacquaint ourselves with basic cardiac physiology at levels ranging from the molecular to the systemic in order to identify new targets for the treatment of HF. This approach has already begun to yield results; in this review, two such aspects will be focused on: diastolic ventricular interaction and cardiac energetics. These two examples will be used to illuminate how fundamental research has elucidated age-old, although mechanistically elusive, principles (for example, the Frank-Starling law), explained why existing and emerging therapeutic approaches (for example, biventricular pacing in HF) have proved successful, and successfully identified novel therapy modes (for example, perhexiline as an energy augmentation agent).


[Adequacy of treatment with ertapenem according to the criterion approved for the infection´s commission of a specialty hospital].
The inappropriate use of antibiotics in our environment increases the risk of multi-resistant bacteria, therefore it is necessary to present studies to meet and promote the proper use of antimicrobial. Retrospective observational study in which patients who are receiving ertapenem during the period of stady (5 ½ months), were included. The adequacy of the indication to the conditions of use agreed in the Hospital was evaluated and the evolution of the treatment was monitored until the end, determining the degree of therapeutic de-escalation. 84 ertapenem prescriptions were included. The vast mayority of the prescriptions were carried out by Internal Medicine (41.7%) and the main indication was urinary tract infection (47.2%). Microbiological cultures were requested in the 75% of the patients before the first dose of ertapenem. The prescription was adapted in 69 (82.14%) of ertapenem patients to the criteria approved by the Hospital. Regarding the evolution of antibiotic therapy, treatment with ertapenem continued until resolution of the infection in 58.33% of patients. In 15 of 23 (66.21%) patients with the possibility of therapeutic de-escalation it was performed after 2-3 days of empirical treatment. The vast majority of treatments ertapenem fit the criteria of prescription our Hospital. The high percentage of patients with microbiological results available, allowed in many patients the appropriate adjustment of the treatment in the first 72 hours.