Reduced affinity of iodinated forms of Tyr0 C-type natriuretic peptide for rat natriuretic peptide receptor B.
Tyr(O)CNP is an analogue of C-type natriuretic peptide (CNP) with a tyrosine residue added to the NH2 terminus to allow its iodination. In the present study, the suitability of iodinated Tyr(O)CNP as a ligand was tested, and its potency was compared with that of other natural rat natriuretic peptides or structural analogues by radioligand binding experiments. Binding studies were performed on membranes of COS-1 cells transfected with expression plasmids for either rat natriuretic peptide receptor (NPR)-A, rat NPR-B, or bovine NPR-C. 125I-ANP(99-126) was used as a ligand to assess the binding characteristics of NPR-A and -C, and 125I-Tyr(O)CNP was used to study NPR-B. Binding associated to membranes of nontransfected COS cells was always < 3% of the total binding observed in membranes from cells transfected with receptor expression plasmids. Receptor densities in transfected cells ranged from 500 to 2500 fmol/mg of protein. High performance liquid chromatography and ionspray mass spectrometry analyses revealed that the reagents used in the course of iodination (lactoperoxidase, chloramine T, or N-chloromorpholine altered the structure of Tyr(O)CNP, most likely by changing the thiol of the Met17 residue into a sulfoxide. To further evaluate the usefulness of forms of iodinated Tyr(O)CNP on the cGMP responses in cells transfected with NPR-B. In conclusion, the suitability iodinated forms of Tyr(O)CNP as radioligands, we performed iodination of the peptide with cold iodine (Na-127I-). After purification by high performance liquid chromatography, three different modified peptides (i.e. Tyr(O)Met(O)17CNP, 127I-Tyr(O)Met(O)17CNP, and 127I2-Tyr(O)Met(O)17CNP) were recovered, and they were compared with CNP-22, Tyr(O)CNP, ANP(99-126), BNP-32, and des[Gin18, Ser19, Gly20, Leu21, Gly22]ANP(4-23) NH2 (c-ANP) for their ability to bind to transfected receptors. The binding affinity of Tyr(O)CNP for NPR-A and -B receptors is similar to that of CNP. However, oxidation of the Met17 residue into methionine sulfoxide reduces the affinity of the compound for NPR-B by > 10-fold, whereas the addition of one or two iodines did not further reduce its affinity. Similar results were obtained on evaluation of the ability of the oxidized form of monoiodinated Tyr(O)CNP on the cGMP responses in cells transfected with NPR-B. In conclusion, the suitability of iodinated forms of Tyr(O)CNP as radioligands for binding studies on rat NPR-B is not optimal, and the results of studies using such compounds for the detection, identification, and quantification of this receptor should be interpreted with caution.


Low-velocity civilian gunshot wounds of the spine.
This article describes a retrospective study on patients admitted to a level I trauma center between 1989 and 1993 with low-velocity gunshot wounds to the spine. Medical records and imaging studies were reviewed to determine patient demographics, neurologic deficit, prophylactic antibiotic administration, and rate of infection, spine stability, and principle associated injuries. A total of 37 patients with low-velocity gunshot wounds to the spine were identified and comprised 34% of all spinal injury patients. Neurologic outcome of the low-velocity gunshot wound to the spine depended on the level of the injury and the presenting neurologic deficit, as improvement of one or two Frankel grades occurred in only seven patients. Prophylactic antibiotics were given to 20 patients, and one infection occurred and was associated with colon perforation. In the absence of hollow viscus perforation, antibiotic prophylaxis did not appear beneficial. Spinal instability was noted in three patients with cervical injury and one patient with lumbar injury, and neurologic deficit was variable despite the presence of instability. The major associated injury was vascular occlusion or disruption in 8 of 12 (66%) cervical low-velocity gunshot wounds to the spine.


Psychometric properties of a Spanish version of the McGill Pain Questionnaire in several Spanish-speaking countries.
Versions of the McGill Pain Questionnaire are available in a several languages and are used in clinical studies and sociocultural or ethnic comparisons of pain issues. However, there is a lack of studies that compare the validity and reliability of the instrument in the countries where it is used. The current study investigates the psychometric properties of a Spanish version of the McGill Pain Questionnaire in five Spanish-speaking countries. The authors conducted a multicenter and transnational study with one investigator in each center. Patients were evaluated once with a Spanish version of the McGill Pain Questionnaire, a visual analog scale, and a verbal rating scale. The study was performed in pain clinics and acute pain units of four Latin American countries (Argentina, Costa Rica, Mexico, and Panama) and Spain. The study included 205 patients (84 with acute pain, 121 with chronic pain) from Latin America. Their data were compared with those of 282 Spanish patients. The McGill Pain Questionnaire, visual analog scale, and verbal rating scale were administered once to all patients. The McGill Pain Questionnaire was administered again to patients from Latin America countries to ascertain descriptor comprehension. Demographic data, McGill Pain Questionnaire parameters, and visual analog scale and a verbal rating scale scores were obtained from patients with chronic and acute pain. Psychometric properties of the Spanish version of the McGill Pain Questionnaire were established for each country by calculating the ordinal consistency by means of rank-scale correlation (Spearman test), intercategory correlation, and interparameter correlation (Pearson test). Concurrent validity was also calculated by comparing scores from the visual analog scale (Pearson test) and verbal rating scale (Spearman test) with questionnaire parameters (qualitative-to-quantitative comparisons). The Spanish version of the McGill Pain Questionnaire maintained a high internal validity when tested in different countries. Ordinal consistency, intercategory, interparameter, and qualitative-to-quantitative parameter correlations were similar in all countries. Few descriptors were considered to be inappropriate or difficult to understand. The psychometric properties of the Spanish version of the McGill Pain Questionnaire assessed in different Latin-American countries suggest that the questionnaire may be used to evaluate Spanish-speaking patients. The validity of this test should be extended with reliability studies to further establish its usefulness in the evaluation of pain.


Promoting occupational health interventions in early return to work by implementing financial subsidies: a Swedish case study.
In 2010, the Swedish government introduced a system of subsidies for occupational health (OH) service interventions, as a part in a general policy promoting early return to work. The aim of this study was to analyse the implementation of these subsidies, regarding how they were used and perceived. The study was carried out using a mixed-methods approach, and comprises material from six sub-studies: a register study of the use of the subsidies, one survey to OH service providers, one survey to employers, one document analysis of the documentation from interventions, interviews with stakeholders, and case interviews with actors involved in coordinated interventions. The subsidized services were generally perceived as positive but were modestly used. The most extensive subsidy--for coordinated interventions--was rarely used. Employers and OH service providers reported few or no effects on services and contracts. OH service providers explained the modest use in terms of already having less bureaucratic routines in place, where applying for subsidies would involve additional costs. Information about the subsidies was primarily communicated to OH service providers, while employers were not informed. The study highlights the complexity of promoting interventions through financial incentives, since their implementation requires that they are perceived by the stakeholders involved as purposeful, manageable and cost-effective. There are inherent political challenges in influencing stakeholders who act on a free market, in that the impact of policies may be limited, unless they are enforced by law.


Intracellular uptake mechanism of lutein in retinal pigment epithelial cells.
Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. It has received much attention recently due to its preventive effect on age-related macular degeneration, and it has been consumed as a supplement. However, little information about the pharmacokinetic properties of lutein is available. Detailed knowledge of pharmacokinetic properties of lutein is needed for the development of pharmaceutics. In this study, we focused on the macular accumulation of lutein and investigated the uptake mechanism into human retinal pigment epithelial cells. ARPE-19 cells were used for the study on the accumulation mechanism of lutein. The concentration of lutein was determined using an HPLC system. Involvement of scavenger class B type 1 (SR-B1) in the accumulation of lutein in ARPE-19 cells was suggested from the results of an inhibition study using block lipid transport 1 (BLT-1), a selective inhibitor of SR-B1. To investigate the involvement of SR-B1 in more detail, small interfering RNA (siRNA) was transfected and the mRNA and protein expression levels of SR-B1 were assessed by quantitative real-time reverse transcription polymerase chain reaction and Western blotting, respectively. We confirmed a sufficient siRNA knockdown effect in both mRNA and protein expression levels of SR-B1. We then found that lutein uptake was significantly decreased by siRNA knockdown of SR-B1. The uptake of lutein was significantly decreased by 40% compared with the control uptake level. This suggested that active transport of lutein into ARPE-19 cells is mainly via SR-B1, given the result that lutein uptake at 4ºC was about 40% less that that at 37ºC.


Career choices for radiology: national surveys of graduates of 1974-2002 from UK medical schools.
To report on trends in career choices for radiology among UK medical graduates. One and 3 years after graduation, and at longer time intervals thereafter, postal questionnaire surveys were sent to all doctors who graduated from UK medical schools in 1974, 1977, 1980, 1983, 1993, 1996, 1999, 2000 and 2002. Doctors were asked to specify their choice of long-term career and to identify factors influencing their choice. Employment details were also collected. Results were analysed using chi(2) statistics and binary logistic regression. Seventy-four percent (24,621/33,412) and 73% (20,720/28,459) of doctors responded 1 and 3 years after graduation. Choices for radiology in year 1 increased significantly over time (1.7% of 1974 graduates to 3.2% of 2002 graduates; chi(2) test for trend=15.3, p<0.001). In particular, there has been a steady increase from the cohorts of 1993 onwards. Thirty-eight percent of those who chose radiology in year 1, and 80% who chose radiology in year 3, were still working in radiology 10 years after graduation. Hours and working conditions influenced long-term career choices more for radiology than for other careers. The proportion of UK trained junior doctors who want to become radiologists has increased in recent years. However, although medical school intake and the numbers making an early choice for radiology have risen, it is unclear whether sufficient UK graduates will be attracted to radiology to fulfil future service requirements from UK trained graduates alone.


Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort Study.
Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0-10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1-16). NCCN Guidelines suggest that patients with DT scores ≥4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score ≥4 and 20 (18%) had 2 or more DT scores ≥4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1-23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01-1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS.


"Nonspatial" Attentional Deficits Interact with Spatial Position in Neglect.
A widely debated question concerns whether or not spatial and nonspatial components of visual attention interact in attentional performance. Spatial neglect is a common consequence of brain injury where individuals fail to respond to stimuli presented on their contralesional side. It has been argued that, beyond the spatial bias, these individuals also tend to exhibit nonspatial perceptual deficits. Here we demonstrate that the "nonspatial" deficits affecting the temporal dynamics of attentional deployment are in fact modulated by spatial position. Specifically, we observed that the pathological attentional blink of chronic neglect is enhanced when stimuli are presented on the contralesional side of the trunk while keeping retinal and head-centered coordinates constant. We did not find this pattern in right brain-damaged patients without neglect or in patients who had recovered from neglect. Our work suggests that the nonspatial attentional deficits observed in neglect are heavily modulated by egocentric spatial position. This provides strong evidence against models that suggest independent modules for spatial and nonspatial attentional functions while also providing strong evidence that trunk position plays an important role in neglect.


Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents.
Reactive oxygen and nitrogen species are overproduced in the cardiovascular system during circulatory shock. Oxidant-induced cell injury involves the activation of poly(ADP-ribose) polymerase (PARP). Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway. Escherichia coli endotoxin (lipopolysaccharide, LPS) at 55 mg/kg, i.p., induced a severe depression of the systolic and diastolic contractile function, tachycardia, and a reduction in mean arterial blood pressure in both rats and mice. Treatment with PJ34 significantly improved cardiac function and increased the survival of rodents. In addition, LPS-induced depression of left ventricular performance was significantly less pronounced in PARP-1 knockout mice (PARP(-/-)) as compared with their wild-type littermates (PARP(+/+)). Thus, PARP activation in the cardiovascular system is an important contributory factor to the cardiac collapse and death associated with endotoxin shock.


Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade.
The Ebf (O/E) family of helix-loop-helix transcription factors plays a significant role in B lymphocyte and neuronal development. The three primary members of this family, Ebf1, 2, and 3, are all expressed in adipocytes, and Ebf1 promotes adipogenesis when overexpressed in NIH 3T3 fibroblasts. Here we report that these three proteins have adipogenic potential in multiple cellular models and that peroxisome proliferator-activated receptor gamma (PPARgamma) is required for this effect, at least in part due to direct activation of the PPARgamma1 promoter by Ebf1. Ebf1 also directly binds to and activates the C/EBPalpha promoter, which exerts positive feedback on C/EBPdelta expression. Despite this, C/EBPalpha is dispensable for the adipogenic action of Ebf proteins. Ebf1 itself is induced by C/EBPbeta and delta, which bind and activate its promoter. Reduction of Ebf1 and Ebf2 proteins by specific short hairpin RNA blocks differentiation of 3T3-L1 cells, suggesting a critical role for these factors and the absence of functional redundancy between members of this family. Altogether, these data place Ebf1 within the known transcriptional cascade of adipogenesis and suggest critical roles for Ebf1 and Ebf2.


[Content determination of different species of Pb, As, and Cd in the municipal sewage sludge of Beijing with ICP-MS].
Heavy metals in municipal sewage sludge can limit the utilization of sludge resources, due to their recalcitrant characteristics and harmful effects. Here, ICP-MS was used to determine the total and special content of Pb, As and Cd in the sewage sludge from G and Q Wastewater Treatment Plants, Beijing. The air-dried samples were dissolved in HNO3-HClO4 before the total content determination, or, sequentially extracted with BCR three-step method before special content determination for the heavy metals. The total contents are 19.60, 37.96 and 1.34 mg x kg(-1) dry weight (DW) for Pb, As and Cd in the sewage sludge from G Plant; respectively; or, 19.58, 23.46 and 2.30 mg x kg(-1) DW in that from Q Plant, respectively. Pb and Cd decreased dramatically in the total contents, compared to the corresponding data in the late 20th century. Both G and Q sludge samples show similar patterns in the species distribution for the three heavy metals: most of Pb and As are HAc soluble, and least are H2O2 oxidative; while Cd mainly exists in NH2OH-HCl reductive state, seldom in HAc soluble state. Species with high ecotoxicity account for a major part (over 70%) of the three species for all the metals on the whole. The authors' results provide basic data for the ecological risk assessment and utilization of municipal sewage sludge from Beijing.


Explanations and unresolved issues pertaining to the development of the Nuclear Pharmacy Compounding Guidelines.
To provide background information related to the development of the Nuclear Pharmacy Compounding Guidelines, to discuss regulatory complexities related to radiopharmaceutical compounding practice, and to summarize the gaps in the current compounding regulations for radiopharmaceuticals. The Guidelines closely follow the provisions of section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the monographs and chapters related to pharmacy compounding in the United States Pharmacopeia (USP), and the recommended guidelines published by the American Society of Health-System Pharmacists. The Food and Drug Administration Modernization Act (FDAMA) of 1997 established parameters under which the compounding of drug products is appropriate and lawful, but these criteria expressly do not apply to radiopharmaceuticals. The Nuclear Pharmacy Compounding Practice Committee, a group of nuclear pharmacists convened by the American Pharmaceutical Association, developed the Nuclear Pharmacy Compounding Guidelines to establish a set of principles and guidelines for good radiopharmaceutical compounding practice. The intent of the new document is to provide guidance on radiopharmaceutical compounding practices that have evolved over the last 2 decades and to place them in an appropriate regulatory framework in accordance with previous enforcement policies and guidelines issued by the U.S. Food and Drug Administration (FDA) regarding the exemption of certain pharmacy practices from enforcement of adulteration, misbranding, and new drug requirements. The Nuclear Pharmacy Compounding Guidelines, recently released by APhA, is the first official document that provides realistic and practical compounding guidance for nuclear pharmacists. Even though the United States Court of Appeals for the Ninth Circuit recently ruled section 503A of the FD&C Act to be invalid in its entirety, and the Supreme Court upheld that ruling, the compliance policy guides issued by FDA in March 1992 and revised in May 2002 maintain guiding principles on pharmacy compounding similar to those stated in section 503A of the FD&C Act. The Nuclear Pharmacy Compounding Practice Committee is optimistic that the practical information contained in the Guidelines will assist state boards of pharmacy, FDA, and the United States Pharmacopeial Convention in setting appropriate standards for nuclear pharmacy compounding practice that will ensure the continued availability of high-quality compounded radiopharmaceuticals at reasonable cost.


Full reconstruction of large lobula plate tangential cells in Drosophila from a 3D EM dataset.
With the advent of neurogenetic methods, the neural basis of behavior is presently being analyzed in more and more detail. This is particularly true for visually driven behavior of Drosophila melanogaster where cell-specific driver lines exist that, depending on the combination with appropriate effector genes, allow for targeted recording, silencing and optogenetic stimulation of individual cell-types. Together with detailed connectomic data of large parts of the fly optic lobe, this has recently led to much progress in our understanding of the neural circuits underlying local motion detection. However, how such local information is combined by optic flow sensitive large-field neurons is still incompletely understood. Here, we aim to fill this gap by a dense reconstruction of lobula plate tangential cells of the fly lobula plate. These neurons collect input from many hundreds of local motion-sensing T4/T5 neurons and connect them to descending neurons or central brain areas. We confirm all basic features of HS and VS cells as published previously from light microscopy. In addition, we identified the dorsal and the ventral centrifugal horizontal, dCH and vCH cell, as well as three VSlike cells, including their distinct dendritic and axonal projection area.


Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2.
SARS-CoV-2 is the cause of a recent pandemic that has led to more than 3 million deaths worldwide. Most individuals are asymptomatic or display mild symptoms, which raises an inherent question as to how does the immune response differs from patients manifesting severe disease? During the initial phase of infection, dysregulated effector immune cells such as neutrophils, macrophages, monocytes, megakaryocytes, basophils, eosinophils, erythroid progenitor cells, and Th17 cells can alter the trajectory of an infected patient to severe disease. On the other hand, properly functioning CD4+, CD8+ cells, NK cells, and DCs reduce the disease severity. Detailed understanding of the immune response of convalescent individuals transitioning from the effector phase to the immunogenic memory phase can provide vital clues to understanding essential variables to assess vaccine-induced protection. Although neutralizing antibodies can wane over time, long-lasting B and T memory cells can persist in recovered individuals. The natural immunological memory captures the diverse repertoire of SARS-CoV-2 epitopes after natural infection whereas, currently approved vaccines are based on a single epitope, spike protein. It is essential to understand the nature of the immune response to natural infection to better identify 'correlates of protection' against this disease. This article discusses recent findings regarding immune response against natural infection to SARS-CoV-2 and the nature of immunogenic memory. More precise knowledge of the acute phase of immune response and its transition to immunological memory will contribute to the future design of vaccines and the identification of variables essential to maintain immune protection across diverse populations.


Crystal structure of a trypanocidal 4,4'-bis(imidazolinylamino)diphenylamine bound to DNA.
The pursuit of small molecules that bind to DNA has led to the discovery of selective and potent antitrypanosomal agents, specifically 4,4'-bis(imidazolinylamino)- and 4,4'-bis(guanidino)diphenylamine compounds, CD27 and CD25, respectively. Although the antitrypanosomal properties of these compounds have been characterized, further development of this series of compounds requires assessment of their DNA site selectivities and affinities. Toward this end, both compounds have been analyzed and found to selectively bind AT sequences. However, CD27 was found to bind with higher affinity to 5'-AATT than 5'-ATAT while CD25 bound more weakly but equally well to either sequence. To detail the nature of its interactions with DNA, the crystal structure of CD27, bound to its preferred DNA-binding site 5'-AATT within a self-complementary oligonucleotide, 5'-d(CTTAATTCGAATTAAG), was determined at 1.75 A using a host-guest approach. Although CD27 is predicted to be highly twisted in its energy-minimized state, it adopts a more planar crescent shape when bound in the minor groove of the DNA. Interactions of CD27 with 5'-AATT include bifurcated hydrogen bonds, providing a basis for selectivity of this site, and favorable van der Waals interactions in a slightly widened minor groove. Thus, an induced fit results from conformational changes in both the ligand and the DNA. Our studies suggest a basis for understanding the mechanism of the antitrypanosomal activity of these symmetric diphenylamine compounds.


Treatment of ADHD in children with tics: a randomized controlled trial.
The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)--the most commonly used drug to treat ADHD--has been reported to worsen tics and because clonidine (CLON)--the most commonly prescribed alternative--has unproven efficacy. The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 x 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy). Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire--Teacher), significant improvement occurred for subjects assigned to CLON (p < 0.002) and those assigned to MPH (p < 0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p < 0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity. Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.


Experimental demonstration of negative refraction imaging in both amplitude and phase.
We studied a two-dimensional square-lattice photonic crystal with all-angle negative refraction at its first band. Using this photonic crystal, we designed and fabricated a flat lens functioning as a cylindrical lens by increasing the vertical dimension of the photonic crystal. Two-dimensional finite-difference time-domain simulation validated negative refraction imaging. To perform the experiment, a microwave imaging system was built based on a vector network analyzer. Field distributions were acquired by scanning the imaging plane and object plane. The experiment demonstrated negative refraction imaging in both amplitude and phase, and obtained an image with feature size, 0.77lambda0.


Evaluating the Relationship of Dental Fear with Dental Health Status and Awareness.
Dental fear is one of the most common problems in dentistry, for both the patient and for the dentist. This issue can have an important effect on an individual's dental health. The aim of this paper was to report on the prevalence of dental anxiety and to explore if high levels of anxiety are associated with sociodemographic factors, oral health status, and level of oral health awareness. The sample for this cross-sectional study included 294 patients (154 males and 140 females). All participants filled out a Dental Fear Survey (DFS) to evaluate their level of dental fear. Gender, age, education level, socioeconomic status and oral health awareness were also noted. Oral health behaviors and oral health awareness levels were investigated using seven questions. Also, the periodontal status of all participants was evaluated using the Community Periodontal Index of Treatment Needs (CPITN). Differences between different subgroups were tested using the chi-square test. There was a statistically significant difference between the DFS groups with regard to sociodemographic data. Women had significantly higher scores than men, and young patients had significantly higher scores than others. Patients with low education levels and low socioeconomic status had high DFS scores. Periodontal status was better in groups that had scores in the low and moderate ranges compared to groups that had high scores on the DFS. There was a statistically significant difference between the groups of DFS and CPITN (p<0.05). Patients with low and moderate levels of DFS answered the oral health knowledge questions correctly. There was a statistically significant difference between the DFS groups based on correct answers to the oral health knowledge questions (p<0.05). The elimination of dental fear is very important and should be treated according to a patient-centered assessment. These individuals were informed about the dental treatment procedure so their prejudices were eliminated. Patients with a high level of dental fear may be given psychiatric support for comfortable treatment procedure.


Liberal or restrictive transfusion in high-risk patients after hip surgery.
The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.).


A shift in the archaeal nitrifier community in response to natural and anthropogenic disturbances in the northern Gulf of Mexico.
The Gulf of Mexico is affected by hurricanes and suffers seasonal hypoxia. The Deepwater Horizon oil spill impacted every trophic level in the coastal region. Despite their importance in bioremediation and biogeochemical cycles, it is difficult to predict the responses of microbial communities to physical and anthropogenic disturbances. Here, we quantify sediment ammonia-oxidizing archaeal (AOA) community diversity, resistance and resilience, and important geochemical factors after major hurricanes and the oil spill. Dominant AOA archetypes correlated with different geochemical factors, suggesting that different AOA are constrained by distinct parameters. Diversity was lowest after the hurricanes, showing weak resistance to physical disturbances. However, diversity was highest during the oil spill and coincided with a community shift, suggesting a new alternative stable state sustained for at least 1 year. The new AOA community was not significantly different from that at the spill site 1 year after the spill. This sustained shift in nitrifier community structure may be a result of oil exposure.


Nation, Narration, and Health in Mohamedou Ould Slahi's Guantánamo Diary.
Scholars have mostly analyzed information from mental health practitioners, attorneys, and institutions to critique mental health practices in the War on Terror. These sources offer limited insights into the suffering of detainees. Detainee accounts provide novel information based on their experiences at Guantánamo. Mohamedou Ould Slahi's Guantánamo Diary is the only text from a current detainee that provides a first-person account of his interrogations and interactions with health professionals. Despite being advertised as a diary, however, it has undergone redaction from American government officials. This article examines Slahi's account of his interrogations and representations of mental health at Guantánamo and considers its role within the narrative function of the nation. At stake is the right of detainees to narrate, scholars to critique medical practices in the War on Terror, and the nation's attempts to control its narration.


DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility.
A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. Here, we profiled DNA methylation changes in a nested case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007-1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007-1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020-1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03-1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.


Single-cell analysis of chromatin accessibility in the adult mouse brain.
Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.


Critical care of patients with AIDS.
We sought to review the clinical and ethical issues surrounding critical care for patients with the acquired immunodeficiency syndrome (AIDS). We reviewed published studies and abstracts dealing with the outcome of critical care for patients with AIDS, decision making about life-sustaining treatments in patients with AIDS, and infection control in the intensive care unit. We also consulted with a number of experts in the field. We selected outcome studies in which patients with documented AIDS or infection with the human immunodeficiency virus (HIV) were analyzed. We rejected data concerning patients with suspected or presumed AIDS and data concerning presumed cases of Pneumocystis carinii pneumonia (PCP). Most AIDS patients who require critical care do so because of respiratory failure caused by PCP. Although studies early in the epidemic reported survival rates to hospital discharge of 0% to 14%, recent studies demonstrate improved survival rates of 36% to 55%. Treatment for patients with PCP and respiratory failure should include either intravenous trimethoprim-sulfa-methoxazole or pentamidine isethionate, as well as adjuvant corticosteroids. Patients with AIDS may require critical care for many other indications, including seizures, sepsis, and hypotension, or reasons unrelated to their immunodeficiency. In general, such patients have a better prognosis than those with respiratory failure. The provision of critical care for PCP and respiratory failure specifically or AIDS generally cannot be considered futile. Therefore, decisions about the use of critical care should be guided by the particular clinical situation and the patient's preferences. More research is needed to elucidate the reasons for the improving survival for patients with PCP and respiratory failure and the predictors of such survival.


Comprehensive Characterization of the RNA Editomes in Cancer Development and Progression.
RNA editing is a post-transcriptional event that leads to transcriptome diversity and has been shown to play important roles in tumorigenesis. However, dynamical changes and the functional significance of editing events during different cancer stages have not yet been characterized systematically. In this paper, we describe a comprehensive study of the RNA editome of four samples from different cancer stages for the same patient based on analysis of both whole-genome and transcriptome sequencing data. We identified 35,225 and 33,784 RNA editing events for poly(A)+ and poly(A)- RNA sequencing data respectively in all four samples and show that 93 and 90% correspond to cancer stage-specific editing events. We also found that half of editing sites in 3' UTR of coding genes were microRNA targets and most of the sites in the coding regions could lead to non-synonymous amino acid changes. Functional analysis of genes which suffered damaging non-synonymous editing events in each cancer stage show the gradual expansion of cancer related pathways accompanied by an increasing malignant grade of the samples. Our study, for the first time to our knowledge, comprehensively profiled and compared the editomes across the different cancer stages and revealed the functional impacts of RNA editing events during cancer development and progression.


Using land to mitigate climate change: hitting the target, recognizing the trade-offs.
Land can be used in several ways to mitigate climate change, but especially under changing environmental conditions there may be implications for food prices. Using an integrated global system model, we explore the roles that these land-use options can play in a global mitigation strategy to stabilize Earth's average temperature within 2 °C of the preindustrial level and their impacts on agriculture. We show that an ambitious global Energy-Only climate policy that includes biofuels would likely not achieve the 2 °C target. A thought-experiment where the world ideally prices land carbon fluxes combined with biofuels (Energy+Land policy) gets the world much closer. Land could become a large net carbon sink of about 178 Pg C over the 21st century with price incentives in the Energy+Land scenario. With land carbon pricing but without biofuels (a No-Biofuel scenario) the carbon sink is nearly identical to the case with biofuels, but emissions from energy are somewhat higher, thereby results in more warming. Absent such incentives, land is either a much smaller net carbon sink (+37 Pg C - Energy-Only policy) or a net source (-21 Pg C - No-Policy). The significant trade-off with this integrated land-use approach is that prices for agricultural products rise substantially because of mitigation costs borne by the sector and higher land prices. Share of income spent on food for wealthier regions continues to fall, but for the poorest regions, higher food prices lead to a rising share of income spent on food.


A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding.
Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.


Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns.
Reports that sweet taste calms crying in newborns and is analgesic against the pain caused by a heel lance served as the basis for this study. Electroencephalographic (EEG) activity, heart rate activity, and infants' facial behaviors were recorded before and after a noninvasive, but noxious, heelstroke (procedure from the Brazelton Neonatal Behavior Assessment Scale). In a randomized and controlled trial, 34 newborns were administered 2 mL of water or sucrose solution before the heelstroke. Frontal EEG asymmetry scores were computed, and power in the 3 to 6 Hz frequency band was analyzed. Infants who received water showed increased relative right frontal EEG activation from baseline to the post-heelstroke phase, a pattern that typifies negative affect. The EEG of infants in the sucrose group did not change. Heart rate increased rapidly in both groups during the heelstroke phase. However, after the heelstroke, the heart rate of infants who received sucrose returned to baseline, whereas the heart rate of infants who tasted water remained elevated. During the heelstroke, the infants in the water group cried and grimaced twice as long as the infants in the sucrose group. These findings add to the growing literature showing that sucrose attenuates newborns' negative response to aversive or noxious stimuli.


Perceptual sequence learning is more severely impaired than motor sequence learning in patients with chronic cerebellar stroke.
Patients with cerebellar stroke are impaired in procedural learning. Several different learning mechanisms contribute to procedural learning in healthy individuals. The aim was to compare the relative share of different learning mechanisms in patients and healthy controls. Ten patients with cerebellar stroke and 12 healthy controls practiced a visuomotor serial reaction time task. Learning blocks with high stimulus-response compatibility were exercised repeatedly; in between these, participants performed test blocks with the same or a different (mirror-inverted or unrelated) stimulus sequence and/or the same or a different (mirror-inverted) stimulus-response allocation. This design allowed to measure the impact of motor learning and perceptual learning independently and to separate both mechanisms from the learning of stimulus-response pairs. Analysis of the learning blocks showed that, as expected, both patients and controls improved their performance over time, although patients remained significantly slower. Analysis of the test blocks revealed that controls showed significant motor learning as well as significant visual perceptual learning, whereas cerebellar patients showed only significant motor learning. Healthy participants were able to use perceptual information for procedural learning even when the rule linking stimuli and responses had been changed, whereas patients with cerebellar lesions could not recruit this perception-based mechanism. Therefore, the cerebellum appears involved in the accurate processing of perceptual information independent from prelearned stimulus-response mappings.


Toward a universal inhibitor of retroviral proteases: comparative analysis of the interactions of LP-130 complexed with proteases from HIV-1, FIV, and EIAV.
One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3' positions, which might be responsible for the variation in the Ki values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds.


Mental time travel and default-mode network functional connectivity in the developing brain.
A core brain network is engaged in remembering the past and envisioning the future. This network overlaps with the so-called default-mode network, the activity of which increases when demands for focused attention are low. Because of their shared brain substrates, an intriguing hypothesis is that default-mode activity, measured at rest, is related to performance in separate attention-focused recall and imagination tasks. However, we do not know how functional connectivity of the default-mode network is related to individual differences in reconstruction of the past and imagination of the future. Here, we show that functional connectivity of the default-mode network in children and adolescents is related to the quality of past remembering and marginally to future imagination. These results corroborate previous findings of a common neuronal substrate for memory and imagination and provide evidence suggesting that mental time travel is modulated by the task-independent functional architecture of the default-mode network in the developing brain. A further analysis showed that local cortical arealization also contributed to explain recall of the past and imagination of the future, underscoring the benefits of studying both functional and structural properties to understand the brain basis for complex human cognition.


The methodological quality of systematic reviews comparing temporomandibular joint disorder surgical and non-surgical treatment.
Temporomandibular joint disorders (TMJD) are multifactor, complex clinical problems affecting approximately 60-70% of the general population, with considerable controversy about the most effective treatment. For example, reports claim success rates of 70% and 83% for non-surgical and surgical treatment, whereas other reports claim success rates of 40% to 70% for self-improvement without treatment. Therefore, the purpose of this study was to (1) identify systematic reviews comparing temporomandibular joint disorder surgical and non-surgical treatment, (2) evaluate their methodological quality, and (3) evaluate the evidence grade within the systematic reviews. A search strategy was developed and implemented for MEDLINE, Cochrane Library, LILACS, and Brazilian Dentistry Bibliography databases. Inclusion criteria were: systematic reviews (+/- meta-analysis) comparing surgical and non-surgical TMJD treatment, published in English, Spanish, Portuguese, Italian, or German between the years 1966 and 2007(up to July). Exclusion criteria were: in vitro or animal studies; narrative reviews or editorials or editorial letters; and articles published in other languages. Two investigators independently selected and evaluated systematic reviews. Three different instruments (AMSTAR, OQAQ and CASP) were used to evaluate methodological quality, and the results averaged. The GRADE instrument was used to evaluate the evidence grade within the reviews. The search strategy identified 211 reports; of which 2 were systematic reviews meeting inclusion criteria. The first review met 23.5 +/- 6.0% and the second met 77.5 +/- 12.8% of the methodological quality criteria (mean +/- sd). In these systematic reviews between 9 and 15% of the trials were graded as high quality, and 2 and 8% of the total number of patients were involved in these studies. The results indicate that in spite of the widespread impact of TMJD, and the multitude of potential interventions, clinicians have expended sparse attention to systematically implementing clinical trial methodology that would improve validity and reliability of outcome measures. With some 20 years of knowledge of evidence-based healthcare, the meager attention to these issues begins to raise ethical issues about TMJD trial conduct and clinical care.


Characteristics of patients with Coronavirus Disease 2019 (COVID-19) and seasonal influenza at time of hospital admission: a single center comparative study.
In the future, co-circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses A/B is likely. From a clinical point of view, differentiation of the two disease entities is crucial for patient management. We therefore aim to detect clinical differences between Coronavirus Disease 2019 (COVID-19) and seasonal influenza patients at time of hospital admission. In this single-center observational study, we included all consecutive patients hospitalized for COVID-19 or influenza between November 2019 and May 2020. Data were extracted from a nationwide surveillance program and from electronic health records. COVID-19 and influenza patients were compared in terms of baseline characteristics, clinical presentation and outcome. We used recursive partitioning to generate a classification tree to discriminate COVID-19 from influenza patients. We included 96 COVID-19 and 96 influenza patients. Median age was 68 vs. 70 years (p = 0.90), 72% vs. 56% (p = 0.024) were males, and median Charlson Comorbidity Index (CCI) was 1 vs. 2 (p = 0.027) in COVID-19 and influenza patients, respectively. Time from symptom onset to hospital admission was longer for COVID-19 (median 7 days, IQR 3-10) than for influenza patients (median 3 days, IQR 2-5, p < 0.001). Other variables favoring a diagnosis of COVID-19 in the classification tree were higher systolic blood pressure, lack of productive sputum, and lack of headache. The tree classified 86/192 patients (45%) into two subsets with ≥80% of patients having influenza or COVID-19, respectively. In-hospital mortality was higher for COVID-19 patients (16% vs. 5%, p = 0.018). Discriminating COVID-19 from influenza patients based on clinical presentation is challenging. Time from symptom onset to hospital admission is considerably longer in COVID-19 than in influenza patients and showed the strongest discriminatory power in our classification tree. Although they had fewer comorbidities, in-hospital mortality was higher for COVID-19 patients.


Effect of cigarette smoke on the mRNA and protein expression of carcinoembryonic antigen (CEA), a possible chemoattractant for neutrophils in human bronchioloalveolar tissues.
The concentration of carcinoembryonic antigen (CEA), known as a marker of malignant transformation and chronic inflammation, is increased in bronchoalveolar lavage fluid obtained from smokers compared with fluid from non-smokers. This study investigated the mechanism and biological significance of CEA production in the lungs of smokers by evaluating protein and mRNA expression in non-carcinomatous lung parenchymal tissues and in cell lines derived from human fetal lung. Lung parenchymal tissue free from cancer or an inflammatory lesion was obtained from five non-smokers (four with lung cancer, one with pulmonary mycetoma), five ex-smokers (all with lung cancer except for one with mesothelioma), and 14 smokers (nine with lung cancer, five with emphysema) at surgery or necropsy. Cancer tissue was also collected simultaneously from the subjects with lung cancer. CEA protein in the tissue homogenates was measured by enzyme linked immunoassay. CEA mRNA expression in the non-carcinomatous parenchymal tissue and cancer tissue was evaluated by in situ hybridisation using CEA specific riboprobe and was semiquantitated by counting the number of silver grains per cell. CEA mRNA expression was also compared in three cell lines derived from human fetal lung (IMR-90, MRC-9, and CCD-14Br) after in vitro stimulation with medium exposed to cigarette smoke or air. Chemoattractant activity of purified CEA for neutrophils and monocytes was also studied in vitro. CEA content in non-carcinomatous lung tissue was increased in smokers with emphysema (mean (SD) 38.0 (9.2) ng/mg protein) or with lung cancer (38.2 (21.6)) compared with non-smokers (11.0 (5.4)) or ex-smokers (5.9 (2.2)). CEA mRNA expression in non-carcinomatous tissue, expressed by average number of grains per cell, was also increased in smokers with emphysema (mean (SD) 11.2 (4.1)) or with lung cancer (14.0 (8.4)) compared with non-smokers (3.1 (0.6)) or ex-smokers (4.0 (1.7)). CEA content in carcinomatous tissues was 42.8 (37.3) for non-smokers, 38.2 (42.4)) for ex-smokers, and 59.0 (22.5) for smokers. The CEA content in carcinomatous tissue was higher than in non-carcinomatous tissue, but there was no difference between non-smokers, ex-smokers, and smokers. The numbers of grains per cell in carcinomatous tissue were higher than in non-carcinomatous tissues, but not different among non-smokers (30.3 (3.9)), ex-smokers (38.3 (13.8)), and smokers (44.3 (5.2)). CEA mRNA expression in the cell lines was upregulated after the incubation with smoke-treated medium. Purified CEA was chemoattractant for neutrophils but not for monocytes in vitro. mRNA and protein expression of CEA were increased in the normal lung tissue from smokers compared with non-smokers or ex-smokers. Since CEA content and mRNA expression were no different between smokers with non-small cell lung cancer and those with non-carcinomatous disease, it is unlikely that CEA expression in non-carcinomatous lung parenchymal tissue was influenced by the presence of the tumour and is consistent with the effect of smoking. This is supported by in vitro studies which show that cigarette smoke could induce CEA mRNA expression in fetal lung derived cells. In addition, CEA might play a part in recruitment of neutrophils into the lower respiratory tract.


The secretions products from invading cercariae of S. japonicum (0-3hRP) restrain mouse dendritic cells to mature.
Schistosomiasis is a water-borne infection caused mainly by human schistosomes including Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum). In the infected host, immune events in the skin appear to have an important initiating role in determining the type, and guiding the magnitude, of the ensuing acquired immune response. The previous studies of S. mansoni showed that dendritic cells (DCs) prime Th2 response after activating with products released by schistosome larvae (material released in the first 3 h after transformation, 0-3hRP). Therefore, it is interesting to know whether 0-3hRP from S. japonicum also activate DC and induce Th2 immune response. Here, we report 0-3hRP of S. japonicum failed to stimulate the maturation of bone marrow-derived DCs (BM-DCs), while soluble antigen of the body of cercariae preparation (SCAP) induced BM-DCs to mature which can be weakened by 0-3hRP. Moreover, using an in vitro ovalbumin peptide-restricted priming assay, DCs treated with 0-3hRP failed to induce T cells to secrete more cytokines than the negative control group by CD4(+) T cells from DO11.10 transgenic mice, while DCs treated with SCAP upregulated secretions of IFN-γ and IL-17A, but downregulated IL-4. Importantly, BM-DCs treated with 0-3hRP plus SCAP induced BM-DCs selective mature which drive Th2-type polarized response. Our in vitro results agree with the findings of in vivo studies by inoculation of DO11.10 mice with different stimulus-activated DCs pulsed with ovalbumin peptide. Our data demonstrate that the secretions from invading cercariae of S. japonicum (0-3hRP) impaired DCs to mature, which is potentially allowing the parasite to negotiate the immune recognition and attack.


Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.
To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. Meta-analysis of individual patient data. Authors of 13 studies (n = 10,002) provided their datasets, and these individual patient data were merged into one dataset. Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤ 1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.


A single gene causes an interspecific difference in pigmentation in Drosophila.
The genetic basis of species differences remains understudied. Studies in insects have contributed significantly to our understanding of morphological evolution. Pigmentation traits in particular have received a great deal of attention and several genes in the insect pigmentation pathway have been implicated in inter- and intraspecific differences. Nonetheless, much remains unknown about many of the genes in this pathway and their potential role in understudied taxa. Here we genetically analyze the puparium color difference between members of the virilis group of Drosophila. The puparium of Drosophila virilis is black, while those of D. americana, D. novamexicana, and D. lummei are brown. We used a series of backcross hybrid populations between D. americana and D. virilis to map the genomic interval responsible for the difference between this species pair. First, we show that the pupal case color difference is caused by a single Mendelizing factor, which we ultimately map to an ∼11-kb region on chromosome 5. The mapped interval includes only the first exon and regulatory region(s) of the dopamine N-acetyltransferase gene (Dat). This gene encodes an enzyme that is known to play a part in the insect pigmentation pathway. Second, we show that this gene is highly expressed at the onset of pupation in light brown taxa (D. americana and D. novamexicana) relative to D. virilis, but not in the dark brown D. lummei. Finally, we examine the role of Dat in adult pigmentation between D. americana (heavily melanized) and D. novamexicana (lightly melanized) and find no discernible effect of this gene in adults. Our results demonstrate that a single gene is entirely or almost entirely responsible for a morphological difference between species.


Improving ambulatory saliva-sampling compliance in pregnant women: a randomized controlled study.
Noncompliance with scheduled ambulatory saliva sampling is common and has been associated with biased cortisol estimates in nonpregnant subjects. This study is the first to investigate in pregnant women strategies to improve ambulatory saliva-sampling compliance, and the association between sampling noncompliance and saliva cortisol estimates. We instructed 64 pregnant women to collect eight scheduled saliva samples on two consecutive days each. Objective compliance with scheduled sampling times was assessed with a Medication Event Monitoring System and self-reported compliance with a paper-and-pencil diary. In a randomized controlled study, we estimated whether a disclosure intervention (informing women about objective compliance monitoring) and a reminder intervention (use of acoustical reminders) improved compliance. A mixed model analysis was used to estimate associations between women's objective compliance and their diurnal cortisol profiles, and between deviation from scheduled sampling and the cortisol concentration measured in the related sample. Self-reported compliance with a saliva-sampling protocol was 91%, and objective compliance was 70%. The disclosure intervention was associated with improved objective compliance (informed: 81%, noninformed: 60%), F(1,60) = 17.64, p<0.001, but not the reminder intervention (reminders: 68%, without reminders: 72%), F(1,60) = 0.78, p = 0.379. Furthermore, a woman's increased objective compliance was associated with a higher diurnal cortisol profile, F(2,64) = 8.22, p<0.001. Altered cortisol levels were observed in less objective compliant samples, F(1,705) = 7.38, p = 0.007, with delayed sampling associated with lower cortisol levels. The results suggest that in pregnant women, objective noncompliance with scheduled ambulatory saliva sampling is common and is associated with biased cortisol estimates. To improve sampling compliance, results suggest informing women about objective compliance monitoring but discourage use of acoustical reminders.


Persulfate oxidation of MTBE- and chloroform-spent granular activated carbon.
Activated persulfate (Na(2)S(2)O(8)) regeneration of methyl tert-butyl ether (MTBE) and chloroform-spent GAC was evaluated in this study. Thermal-activation of persulfate was effective and resulted in greater MTBE removal than either alkaline-activation or H(2)O(2)-persulfate binary mixtures. H(2)O(2) may serve multiple roles in oxidation mechanisms including Fenton-driven oxidation, and indirect activation of persulfate through thermal or ferrous iron activation mechanisms. More frequent, lower volume applications of persulfate solution (i.e., the persulfate loading rate), higher solid/solution ratio (g GAC mL(-1) solution), and higher persulfate concentration (mass loading) resulted in greater MTBE oxidation and removal. Chloroform oxidation was more effective in URV GAC compared to F400 GAC. This study provides baseline conditions that can be used to optimize pilot-scale persulfate-driven regeneration of contaminant-spent GAC.


2-(1-(2-Benzhydrylnaphthylimino)ethyl)pyridylnickel halides: synthesis, characterization, and ethylene polymerization behavior.
A series of 2-(1-(2-benzhydrylnaphthylimino)ethyl)pyridine derivatives (L1-L3) was synthesized and fully characterized. The organic compounds acted as bi-dentate ligands on reacting with nickel halides to afford two kinds of nickel complexes, either mononuclear bis-ligated L2NiBr2 (Ni1-Ni3) or chloro-bridged dinuclear L2Ni2Cl4 (Ni4-Ni6) complexes. The nickel complexes were fully characterized, and the single crystal X-ray diffraction revealed for Ni2, a distorted square pyramidal geometry at nickel comprising four nitrogens of two ligands and one bromide; whereas for Ni4, a centrosymmetric dimer possessing a distorted octahedral geometry at nickel was formed by two nitrogens of one ligand, two bridging chlorides and one terminal chloride along with oxygen from methanol (solvent). When activated with diethylaluminium chloride (Et2AlCl), all nickel complexes performed with high activities (up to 1.22 × 10(7) g (PE) mol(-1) (Ni) h(-1)) towards ethylene polymerization; the obtained polyethylene possessed high branching, low molecular weight and narrow polydispersity, suggestive of a single-site active species. The effect of the polymerization parameters, including the nature of the ligands/halides on the catalytic performance is discussed.


Are cuckoos maximizing egg mimicry by selecting host individuals with better matching egg phenotypes?
Avian brood parasites and their hosts are involved in complex offence-defense coevolutionary arms races. The most common pair of reciprocal adaptations in these systems is egg discrimination by hosts and egg mimicry by parasites. As mimicry improves, more advanced host adaptations evolve such as decreased intra- and increased interclutch variation in egg appearance to facilitate detection of parasitic eggs. As interclutch variation increases, parasites able to choose hosts matching best their own egg phenotype should be selected, but this requires that parasites know their own egg phenotype and select host nests correspondingly. We compared egg mimicry of common cuckoo Cuculus canorus eggs in naturally parasitized marsh warbler Acrocephalus palustris nests and their nearest unparasitized conspecific neighbors having similar laying dates and nest-site characteristics. Modeling of avian vision and image analyses revealed no evidence that cuckoos parasitize nests where their eggs better match the host eggs. Cuckoo eggs were as good mimics, in terms of background and spot color, background luminance, spotting pattern and egg size, of host eggs in the nests actually exploited as those in the neighboring unparasitized nests. We reviewed the evidence for brood parasites selecting better-matching host egg phenotypes from several relevant studies and argue that such selection probably cannot exist in host-parasite systems where host interclutch variation is continuous and overall low or moderate. To date there is also no evidence that parasites prefer certain egg phenotypes in systems where it should be most advantageous, i.e., when both hosts and parasites lay polymorphic eggs. Hence, the existence of an ability to select host nests to maximize mimicry by brood parasites appears unlikely, but this possibility should be further explored in cuckoo-host systems where the host has evolved discrete egg phenotypes.


Increasing PCR sensitivity by removal of polymerase inhibitors in environmental samples by using dielectrophoresis.
Dielectrophoresis (DEP) is a powerful tool to manipulate cells and molecules in microfluidic chips. However, few practical applications using DEP exist. An immediate practical application of a carbon-electrode DEP system, in removing PCR inhibitors from a sample, is reported in this work. We use a high throughput carbon-electrode DEP system to trap yeast cells from a natural sample (fermented grape must) and then in situ remove contaminants that interfere with PCR analysis. Retrieval of this enriched and purified yeast population from the DEP system then allows for a significant increase of sensitivity during PCR analysis. Furthermore, the fact that DEP can discriminate between viable and non-viable cells minimizes the number of false positives commonly obtained when using PCR alone. Experimental results provide clear evidence that the carbon-electrode DEP-based sample preparation step can readily and effectively clean environmental samples from natural contaminants and improve PCR sensitivity.


Epidemiology, genetic diversity, and evolution of endemic feline immunodeficiency virus in a population of wild cougars.
Within the large body of research on retroviruses, the distribution and evolution of endemic retroviruses in natural host populations have so far received little attention. In this study, the epidemiology, genetic diversity, and molecular evolution of feline immunodeficiency virus specific to cougars (FIVpco) was examined using blood samples collected over several years from a free-ranging cougar population in the western United States. The virus prevalence was 58% in this population (n = 52) and increased significantly with host age. Based on phylogenetic analysis of fragments of envelope (env) and polymerase (pol) genes, two genetically distinct lineages of FIVpco were found to cooccur in the population but not in the same individuals. Within each of the virus lineages, geographically nearby isolates formed monophyletic clusters of closely related viruses. Sequence diversity for env within a host rarely exceeded 1%, and the evolution of this gene was dominated by purifying selection. For both pol and env, our data indicate mean rates of molecular evolution of 1 to 3% per 10 years. These results support the premise that FIVpco is well adapted to its cougar host and provide a basis for comparing lentivirus evolution in endemic and epidemic infections in natural hosts.


Novel reversible and switchable electrolytes based on magneto-rheology.
Replacing organic liquid electrolytes with solid electrolytes has led to a new perspective on batteries, enabling high-energy battery chemistry with intrinsically safe cell designs. However, most solid/gel electrolytes are easily deformed; under extreme deformation, leakage and/or short-circuiting can occur. Here, we report a novel magneto-rheological electrolyte (MR electrolyte) that responds to changes in an external magnetic field; the electrolyte exhibits low viscosity in the absence of a magnetic field and increased viscosity or a solid-like phase in the presence of a magnetic field. This change from a liquid to solid does not significantly change the conductivity of the MR electrolyte. This work introduces a new class of magnetically sensitive solid electrolytes that can enhance impact resistance and prevent leakage from electronic devices through reversible active switching of their mechanical properties.


A multi-institutional analysis of 429 patients undergoing major hepatectomy for colorectal cancer liver metastases: The impact of concomitant bile duct resection on survival.
Data are lacking on long-term outcomes of patients undergoing major hepatectomy requiring bile duct resection (BDR) for the treatment of colorectal cancer liver metastases. Patients who underwent major hepatectomy (≥3 segments) for metastatic colorectal cancer from 2000-2010 at three US academic institutions were included. The primary outcome was disease-specific survival (DSS). Of 429 patients, nine (2.1%) underwent BDR, which was associated with pre-operative portal vein embolization (25.0% vs. 4.3%; P = 0.049). There were no significant differences in age, ASA class, margin status, number of lesions, tumor size, cirrhosis, perineural invasion, or lymphovascular invasion. BDR was independently associated with increased postoperative major complications (OR: 6.22; 95%CI:1.44-26.97; P = 0.015). There were no differences in length of stay, reoperation, readmission, or 30-day mortality. Patients who underwent BDR had markedly decreased DSS (9.3 vs. 39.9 mo; P = 0.002). When accounting for differences between the two groups, the need for BDR was independently associated with reduced DSS (HR: 3.06; 95%CI:1.12-8.34; P = 0.029). Major hepatectomy with concomitant bile duct resection is seldom performed in patients undergoing resection of colorectal cancer liver metastases and is associated with higher major morbidity and reduced disease-specific survival compared to major hepatectomy alone. Stringent selection criteria should be applied when patients may need bile duct resection during hepatectomy for colorectal cancer liver metastases.


Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.
Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorder (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at midgestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.


Effects of anabolic-androgenic steroids on muscular strength.
To assess the effects of anabolic-androgenic steroids on human muscle strength. A MEDLINE search for the period from January 1966 to April 1990, supplemented by manual searches of previous reviews, produced 30 studies in which subjects received more than one dose of the study steroid and in which changes in muscular strength were measured. Of the 30 studies, 14 were not included in the detailed data summary because they did not use a placebo control, did not randomize subjects to groups, or did not make objective strength measurements, or because percent change in strength data could not be abstracted. Details of study design, reporting of results, and the adequacy and correctness of statistical methods were tabulated. Percent improvement in strength for the largest muscle group studied was computed, using the difference between results for the placebo and for the steroid-treated groups. Previously trained athletes show slightly greater improvements in strength in the anabolic-androgenic steroid-treated group than in the placebo group, with a median difference of 5% across the nine studies (range, 1.2% to 18.7%). A meta-analysis of the three studies with enough information to compute effect size showed a mean difference of 1.0 standard deviations (95% CI, 0.49 to 1.5). However, the poor overall quality of the studies in terms of design, sample size, and analysis; the lack of a dose-response effect across the narrow range of dosages tested; and the tendency for differences to be smaller in the larger studies throw these results into question. No evidence was found to support enhanced muscle strength with steroid use in eight studies in untrained normal volunteers. Anabolic steroids may slightly enhance muscle strength in previously trained athletes. No firm conclusion is possible concerning the efficacy of anabolic steroids in enhancing overall athletic performance. Results for the low steroid dosages studied in the published reports cannot be generalized to steroid-using athletes taking megadose regimens.


Sexual and reproductive life of women informed of their HIV seropositivity: a prospective cohort study in Burkina Faso.
In the context of the DITRAME-ANRS 049 research program that evaluated interventions aimed at reducing mother-to-child transmission of HIV (MTCT) in Bobo-Dioulasso (Burkina Faso), Voluntary HIV counseling and testing (VCT) services were established for pregnant women. HIV-infected women were advised to disclose their HIV serostatus to their male partners who were also offered VCT, to use condoms to reduce sexual transmission, and to choose an effective contraception method to avoid unwanted pregnancies. This study aimed at assessing how HIV test results were shared with male sexual partners, the level of use of modern contraceptive methods, and the pregnancy incidence among these women informed of the risks surrounding sexual and reproductive health during HIV infection. From 1995 to 1999, a quarterly prospective follow-up of a cohort of HIV-positive women. Overall, 306 HIV-positive women were monitored over an average period of 13.5 months following childbirth, accounting for a total of 389 person-years. The mean age at enrollment in the cohort was 25.1 (standard deviation, 5.2 years). In all, 18% of women informed their partners, 8% used condoms at each instance of sexual intercourse to avoid HIV transmission, and 39% started using hormonal contraception. A total of 48 pregnancies occurred after HIV infection was diagnosed, an incidence of 12.3 pregnancies per 100 person-years. Pregnancy incidence was 4 per 100 person-years in the first year of monitoring and this rose significantly to 18 per 100 person-years in the third year. The only predictor of the occurrence of a pregnancy after HIV diagnosis was the poor outcome of the previous pregnancy (stillbirth, infant death). Severe immunodeficiency and change in marital status were the only factors that prevented the occurrence of a pregnancy after HIV diagnosis. Our study shows a poor rate of HIV test sharing and a poor use of contraceptive methods despite regular advice and counseling. Pregnancy incidence remained comparable with the pregnancy rate in the general population. To improve this situation, approaches for involving husbands or partners in VCT and prevention of MTCT interventions should be developed, evaluated, and implemented.


Physiology is rocking the foundations of evolutionary biology.
The 'Modern Synthesis' (Neo-Darwinism) is a mid-20th century gene-centric view of evolution, based on random mutations accumulating to produce gradual change through natural selection. Any role of physiological function in influencing genetic inheritance was excluded. The organism became a mere carrier of the real objects of selection, its genes. We now know that genetic change is far from random and often not gradual. Molecular genetics and genome sequencing have deconstructed this unnecessarily restrictive view of evolution in a way that reintroduces physiological function and interactions with the environment as factors influencing the speed and nature of inherited change. Acquired characteristics can be inherited, and in a few but growing number of cases that inheritance has now been shown to be robust for many generations. The 21st century can look forward to a new synthesis that will reintegrate physiology with evolutionary biology.


A coclustering approach for mining large protein-protein interaction networks.
Several approaches have been presented in the literature to cluster Protein-Protein Interaction (PPI) networks. They can be grouped in two main categories: those allowing a protein to participate in different clusters and those generating only nonoverlapping clusters. In both cases, a challenging task is to find a suitable compromise between the biological relevance of the results and a comprehensive coverage of the analyzed networks. Indeed, methods returning high accurate results are often able to cover only small parts of the input PPI network, especially when low-characterized networks are considered. We present a coclustering-based technique able to generate both overlapping and nonoverlapping clusters. The density of the clusters to search for can also be set by the user. We tested our method on the two networks of yeast and human, and compared it to other five well-known techniques on the same interaction data sets. The results showed that, for all the examples considered, our approach always reaches a good compromise between accuracy and network coverage. Furthermore, the behavior of our algorithm is not influenced by the structure of the input network, different from all the techniques considered in the comparison, which returned very good results on the yeast network, while on the human network their outcomes are rather poor.


Binge alcohol-induced microvesicular liver steatosis and injury are associated with down-regulation of hepatic Hdac 1, 7, 9, 10, 11 and up-regulation of Hdac 3.
Binge, as well as chronic, alcohol consumption affects global histone acetylation leading to changes in gene expression. It is becoming increasingly evident that these histone-associated epigenetic modifications play an important role in the development of alcohol-mediated hepatic injury. C57BL/6 mice were gavaged 3 times (12-hour intervals) with ethanol (EtOH; 4.5 g/kg). Hepatic histone deacetylase (Hdac) mRNAs were assessed by qRT-PCR. Total HDAC activity was estimated by a colorimetric HDAC activity/inhibition assay. Histone acetylation levels were evaluated by Western blot. Liver steatosis and injury were evaluated by histopathology, plasma aminotransferase (ALT) activity, and liver triglyceride accumulation. Expression of fatty acid synthase (Fas) and carnitine palmitoyl transferase 1a (Cpt1a) was also examined. HDAC 9 association with Fas promoter was analyzed. Binge alcohol exposure resulted in alterations of hepatic Hdac mRNA levels. Down-regulation of HDAC Class I (Hdac 1), Class II (Hdac 7, 9, 10), and Class IV (Hdac 11) and up-regulation of HDAC Class I (Hdac 3) gene expression were observed. Correspondent to the decrease in HDAC activity, an increase in hepatic histone acetylation was observed. These molecular events were associated with microvesicular hepatic steatosis and injury characterized by increased hepatic triglycerides (48.02 ± 3.83 vs. 19.90 ± 3.48 mg/g liver, p < 0.05) and elevated plasma ALT activity (51.98 ± 6.91 vs. 20.8 ± 0.62 U/l, p < 0.05). Hepatic steatosis was associated with an increase in FAS and a decrease in CPT1a mRNA and protein expression. Fas promoter analysis revealed that binge EtOH treatment decreased HDAC 9 occupancy at the Fas promoter resulting in its transcriptional activation. Deregulation of hepatic Hdac expression likely plays a major role in the binge alcohol-induced hepatic steatosis and liver injury by affecting lipogenesis and fatty acid β-oxidation.


Neutrality, cross-immunity and subtype dominance in avian influenza viruses.
Avian influenza viruses (AIVs) are considered a threat for their potential to seed human influenza pandemics. Despite their acknowledged importance, there are significant unknowns regarding AIV transmission dynamics in their natural hosts, wild birds. Of particular interest is the difference in subtype dynamics between human and bird populations-in human populations, typically only two or three subtypes cocirculate, while avian populations are capable of simultaneously hosting a multitude of subtypes. One species in particular-ruddy turnstones (Arenaria interpres)--has been found to harbour a very wide range of AIV subtypes, which could make them a key player in the spread of new subtypes in wild bird populations. Very little is known about the mechanisms that drive subtype dynamics in this species, and here we address this gap in our knowledge. Taking advantage of two independent sources of data collected from ruddy turnstones in Delaware Bay, USA, we examine patterns of subtype diversity and dominance at this site. We compare these patterns to those produced by a stochastic, multi-strain transmission model to investigate possible mechanisms that are parsimonious with the observed subtype dynamics. We find, in agreement with earlier experimental work, that subtype differences are unnecessary to replicate the observed dynamics, and that neutrality alone is sufficient. We also evaluate the role of subtype cross-immunity and find that it is not necessary to generate patterns consistent with observations. This work offers new insights into the mechanisms behind subtype diversity and dominance in a species that has the potential to be a key player in AIV dynamics in wild bird populations.


Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.
The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial suggested a small increased risk of myocardial infarction (MI) with the use of dabigatran etexilate vs warfarin in patients with atrial fibrillation. We systematically evaluated the risk of MI or acute coronary syndrome (ACS) with the use of dabigatran. We searched PubMed, Scopus, and the Web of Science for randomized controlled trials of dabigatran that reported on MI or ACS as secondary outcomes. The fixed-effects Mantel-Haenszel (M-H) test was used to evaluate the effect of dabigatran on MI or ACS. We expressed the associations as odds ratios (ORs) and their 95% CIs. Seven trials were selected (N = 30,514), including 2 studies of stroke prophylaxis in atrial fibrillation, 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of deep venous thrombosis. Control arms included warfarin, enoxaparin, or placebo administration. Dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 237 of 20,000 [1.19%] vs control, 83 of 10,514 [0.79%]; OR(M-H), 1.33; 95% CI, 1.03-1.71; P = .03). The risk of MI or ACS was similar when using revised RE-LY trial results (OR(M-H), 1.27; 95% CI, 1.00-1.61; P = .05) or after exclusion of short-term trials (OR(M-H), 1.33; 95% CI, 1.03-1.72; P = .03). Risks were not heterogeneous for all analyses (I(2) = 0%; P ≥ .30) and were consistent using different methods and measures of association. Dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls. Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran.


Wiedemann-steiner syndrome with a de novo mutation in KMT2A: A case report.
Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.


Health worker recruitment and deployment in remote areas of Indonesia.
Providing health care in remote and very remote areas has long been a major concern in Indonesia. In order to improve access to quality health care for residents in these areas, various policies on recruitment and deployment of health workers have been implemented, among them compulsory service, contracted staff and the Special Assignment of strategic health workers. Indonesia's difficult geography presents great challenges to health service delivery and most health workers prefer to serve in urban areas, resulting in an uneven distribution of health workers and shortages in remote areas. Great efforts have been made to mobilize health human resources more equitably, including placement schemes for strategic health workers and contracted staff, combined with an incentive scheme. While these have partially addressed the severe shortage of health workers in remote areas, current government policies were reviewed in order to clarify the current situation in Indonesia. The Contracted Staff and Special Assignment of Strategic Health Workers programs show have made a significant contribution to improving the availability of health workers in Indonesia's remote areas. As these two programs used financial incentives as the main intervention, other non-financial interventions should also be trialed. For example, incentives such as the promise of a civil servant appointment or the provision of continuing professional education, as well as the recruitment of rural-background health workers may increase the willingness of health staff to serve in the remote and very remote areas of Indonesia.


Assessment of treatment options for patients with hepatitis C virus recombinant form 2k/1b.
Hepatitis C virus (HCV) intergenotype recombinant form (RF) 2k/1b has been actively circulating in HCV-infected patients, and the prevalence of this RF virus in the Republic of Georgia is one of the highest reported worldwide. The aim of this study was to define the optimal treatment regimen for patients with RF_2k/1b. We analyzed the data of 2735 patients who started treatment at the Medical Center Mrcheveli within Georgia's hepatitis C elimination program from May 2015 through December 2019. The patients were treated with sofosbuvir (SOF)-based regimens. For identification of RF_2k/1b variants, refinement of standard (INNO-LiPA) genotyping results for all patient samples assigned the unspecific HCV genotypes (GT) 2a/2c was carried out by sequencing of core and non-structural protein 5B genes. Overall, 444 patients, representing 66% of GT2 and 16% of the total samples, were RF_2k/1b. Treatment of patients with RF_2k/1b with SOF/ledipasvir and SOF/velpatasvir was highly effective and viral cure rates did not differ among genotypes treated with the same regimen: RF_2k/1b, 99% (343/346); GT1, 99% (876/885); GT2, 96% (156/162); and GT3, 99% (545/552). A separate comparison analysis of sustained virologic response rate, treated with SOF plus ribavirin, showed significantly higher sustained virologic response (96%) in patients with confirmed GT2 (by sequencing) compared to unspecified GT2 (by INNO-LiPA) (79%) (P < 0.05). Sofosbuvir-based regimens are highly effective for treatment of RF 2k/1b patients, and with availability of new pan-genotypic direct-acting antivirals, genotyping to identify RF 2k/1b patients might not be necessary.