Prevention of delirium in hospitalized older patients: risk factors and targeted intervention strategies.
Delirium is a common, costly, and potentially devastating condition for hospitalized older patients. Delirium is a multifactorial syndrome, involving the inter-relationship between patient vulnerability, or predisposing factors at admission, and noxious insults or precipitating factors during hospitalization. Through a series of studies, we first identified significant predisposing factors for delirium, including vision impairment, severe illness, cognitive impairment, and dehydration. Subsequently, significant precipitating factors were identified, including physical restraint use, malnutrition, adding more than three drugs, bladder catheter use, and any iatrogenic event. Through targeting preventive strategies towards six identified risk factors in a controlled clinical trial, we were successful in the primary prevention of delirium. In 852 subjects, the incidence of delirium was significantly reduced in the intervention group compared with usual care (9.9% vs 15.0%, matched odds ratio: 0.60; 95% confidence interval: 0.39-0.92). The total number of days and episodes of delirium were also significantly reduced in the intervention group. Based on this work, evidence-based recommendations for delirium prevention are proposed. While not all cases of delirium will be preventable with this approach, unifying medical and epidemiological approaches to delirium represents a key advance essential to reducing the high morbidity and mortality associated with delirium in the older population.


Risk of cancer in patients with heart failure who use digoxin: a 10-year follow-up study and cell-based verification.
Heart failure (HF) is the leading cause of death in the world and digoxin remains one of the oldest therapies for HF. However, its safety and efficacy have been controversial since its initial use and there is uncertainty about its long-term efficacy and safety. Recently, the repositioning of cardiac glycosides is to function in anti-tumor activity via multiple working pathways. It is interesting to compare the potential effects of digoxin in clinical patients and cell lines. First, we analyze patient information retrieved from the National Health Insurance Research database of Taiwan between January 1, 2000 and December 31, 2000. This retrospective study included a study cohort (1,219 patients) and a comparison cohort. Our analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, we further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, we combined a cohort study for digoxin treatment for HF patients with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.


Quantum and classical confinement of resonant states in a trilayer graphene Fabry-Pérot interferometer.
The advent of few-layer graphene has given rise to a new family of two-dimensional systems with emergent electronic properties governed by relativistic quantum mechanics. The multiple carbon sublattices endow the electronic wavefunctions with pseudospin, a lattice analogue of the relativistic electron spin, whereas the multilayer structure leads to electric-field-effect tunable electronic bands. Here we use these properties to realize giant conductance oscillations in ballistic trilayer graphene Fabry-Pérot interferometers, which result from phase coherent transport through resonant bound states beneath an electrostatic barrier. We confine these states by selectively decoupling them from the leads, resulting in transport via non-resonant states and suppression of the giant oscillations. The confinement is achieved both classically, by manipulating quasiparticle momenta with a magnetic field, and quantum mechanically, by locally varying the pseudospin character of the carrier wavefunctions. Our results illustrate the unique potential of trilayer graphene as a versatile platform for electron optics and pseudospintronics.


Microfluidic array cytometer based on refractive optical tweezers for parallel trapping, imaging and sorting of individual cells.
Analysis of genetic and functional variability in populations of living cells requires experimental techniques capable of monitoring cellular processes such as cell signaling of many single cells in parallel while offering the possibility to sort interesting cell phenotypes for further investigations. Although flow cytometry is able to sequentially probe and sort thousands of cells per second, dynamic processes cannot be experimentally accessed on single cells due to the sub-second sampling time. Cellular dynamics can be measured by image cytometry of surface-immobilized cells, however, cell sorting is complicated under these conditions due to cell attachment. We here developed a cytometric tool based on refractive multiple optical tweezers combined with microfluidics and optical microscopy. We demonstrate contact-free immobilization of more than 200 yeast cells into a high-density array of optical traps in a microfluidic chip. The cell array could be moved to specific locations of the chip enabling us to expose in a controlled manner the cells to reagents and to analyze the responses of individual cells in a highly parallel format using fluorescence microscopy. We further established a method to sort single cells within the microfluidic device using an additional steerable optical trap. Ratiometric fluorescence imaging of intracellular pH of trapped yeast cells allowed us on the one hand to measure the effect of the trapping laser on the cells' viability and on the other hand to probe the dynamic response of the cells upon glucose sensing.


Shark Conservation: An Educational Approach Based on Children's Knowledge and Perceptions toward Sharks.
Shark conservation has become a focus of current international conservation efforts. However, the misunderstanding of sharks and their negative public portrayal may hinder their conservation. More importantly, the consumption of shark fin, which is very common in Chinese cultures, poses a significant threat to sharks. Hong Kong has long been the world's largest shark fin trading center. Shark conservation would become more sustainable if public understanding of this predatory fish and an appreciation of its ecological significance could be promoted. It is possible that the demand for fins could be effectively managed through long-term educational efforts targeted at younger generations. To provide essential baseline data for planning of these educational efforts, this project investigated the perceptions of 11 to 12 year-old primary school students in Hong Kong about sharks, and their understanding of ecological concepts and shark-related knowledge. The findings indicate that these students lack sufficient knowledge and possess misconceptions about sharks and their ecological significance in the marine ecosystem. The students' conceptual understanding level is strongly correlated with their perceptions. Correlational analyses further demonstrated a positive association between formal education and perceptions toward shark conservation. The students who favoured shark fin consumption did so because of its tastiness, whereas concerns about shark population decline and the cruelty of shark hunting were the main reasons for not favoring shark fin consumption. This pilot study provides preliminary but important insights into primary school education regarding the conservation of sharks.


The paediatric airway: basic principles and current developments.
Perioperative airway problems frequently result in significant morbidity and mortality in children. Therefore, proficiency in airway management is one of the most important key elements in the safe conduct of paediatric anaesthesia. This review includes important anatomical and physiological aspects of the paediatric airway, challenges encountered, and their management with commonly available resources. The importance of early recognition and treatment of anatomical or functional airway obstruction using locally adapted algorithms is highlighted. Children deemed at risk of aspiration require a controlled rapid sequence induction with sufficiently deep anaesthesia, confirmed complete muscle paralysis and intermittent ventilation prior to tracheal intubation. The benefits of a supraglottic airway device and a cuffed tracheal tube in paediatric airway management are discussed. The primary goal of mastering the paediatric airway is to ensure oxygenation and ventilation. This requires intricate knowledge, regular practice and experience.


Evidence for indigenous nitrogen in sedimentary and aeolian deposits from the Curiosity rover investigations at Gale crater, Mars.
The Sample Analysis at Mars (SAM) investigation on the Mars Science Laboratory (MSL) Curiosity rover has detected oxidized nitrogen-bearing compounds during pyrolysis of scooped aeolian sediments and drilled sedimentary deposits within Gale crater. Total N concentrations ranged from 20 to 250 nmol N per sample. After subtraction of known N sources in SAM, our results support the equivalent of 110-300 ppm of nitrate in the Rocknest (RN) aeolian samples, and 70-260 and 330-1,100 ppm nitrate in John Klein (JK) and Cumberland (CB) mudstone deposits, respectively. Discovery of indigenous martian nitrogen in Mars surface materials has important implications for habitability and, specifically, for the potential evolution of a nitrogen cycle at some point in martian history. The detection of nitrate in both wind-drifted fines (RN) and in mudstone (JK, CB) is likely a result of N2 fixation to nitrate generated by thermal shock from impact or volcanic plume lightning on ancient Mars. Fixed nitrogen could have facilitated the development of a primitive nitrogen cycle on the surface of ancient Mars, potentially providing a biochemically accessible source of nitrogen.


Serum markers in community-acquired pneumonia and ventilator-associated pneumonia.
This article reviews recent data on the usefulness of serum markers in community-acquired pneumonia and ventilator-associated pneumonia. The focus is on clinical studies, with an emphasis on adult critically ill patients. Serum markers have demonstrated potential value in early prediction and diagnosis of pneumonia, in monitoring the clinical course and in guiding antibiotic therapy. C-reactive protein appears to perform better in diagnosing infection, because several studies have shown that procalcitonin may remain undetectable in some patients, specifically those with pneumonia. Procalcitonin exhibited a better correlation with clinical severity, however. Furthermore, one report demonstrated the efficacy and safety of procalcitonin-guided antibiotic therapy in community-acquired pneumonia. Serum markers should only be used as a complementary tool to support the current clinical approach. Use of serum markers, in particular procalcitonin and C-reactive protein, represents a promising strategy in the clinical decision-making process in patients in whom pneumonia is suspected. Specifically, these markers can be used to guide culture sampling and empirical antibiotic prescription, and to monitor the clinical course, adjust the duration of antibiotic therapy and identify nonresponders, in whom an aggressive diagnostic and therapeutic approach may prevent further clinical deterioration.


Thermal averages in a quantum point contact with a single coherent wave packet.
A novel formal equivalence between thermal averages of coherent properties (e.g., conductance) and time averages of a single wave packet arises for Fermi gases and certain geometries. In the case of one open channel in a quantum point contact (QPC), only one wave packet history, with the wave packet width equal to the thermal length, completely determines the thermally averaged conductance. The formal equivalence moreover allows very simple physical interpretations of interference features surviving under thermal averaging. Simply put, pieces of the thermal wave packet returning to the QPC along independent paths must arrive at the same time in order to interfere. Remarkably, one immediate result of this approach is that higher temperature leads to narrower wave packets and therefore better resolution of events in the time domain. In effect, experiments at 4.2 K are performing time-gated experiments at better than a gigahertz. Experiments involving thermally averaged ballistic conductance in 2DEGS are presented as an application of this picture.


Accuracy and Reproducibility of Radiographic Images for Assessing Crestal Bone Height of Implants Using the Precision Implant X-ray Locator (PIXRL) Device.
Assessment of crestal bone levels around implants is essential to monitor success and health. This is best accomplished with intraoral radiographs exposed at 90 degrees to the long axis of the implant, but this can be challenging to achieve clinically. Radiographic paralleling devices produce orthogonal radiographs but traditionally have required access to the implant body for each exposure. This study was conducted to determine if use of the Precision Implant X-ray Locator (PIXRL), a radiographic paralleling device that indexes the implant at the time of surgical placement, can produce orthogonal radiographs of dental implants more accurately than traditional radiologic techniques for assessing crestal bone levels. Three dental implants were inserted in dry human skulls in supracrestal positions to simulate crestal bone loss (maxillary right first premolar [site 14], maxillary right central incisor [site 11], and mandibular left second premolar [site 35]). The implants were masked with a soft tissue moulage and restored with provisional restorations. Four dental assistants exposed six radiographs using their usual and customary technique and six using the PIXRL device for each implant. A single examiner measured crestal bone levels on the radiographs relative to the implant platform shoulder on the mesial and distal of each implant. Recorded measurements were compared to the known values. Statistical analysis was completed using a generalized linear regression model to analyze the differences, and post-hoc comparisons with pairwise adjustment were applied. The images produced using the PIXRL device were more accurate overall compared to traditional techniques and were also more consistent. The greater degree of accuracy was statistically significant for all sites with the exception of the mesial measurements of the implant at site 11. This study demonstrates that the use of the PIXRL device can assist clinicians in obtaining more accurate orthogonal radiographs for assessing crestal bone height and would be a useful tool for researchers utilizing radiographic imaging of implants as a longitudinal measure of implant success and stability.


Precision Medicine in Active Surveillance for Prostate Cancer: Development of the Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator.
Men on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly. To use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes. Biopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed. Logistic regression was used to predict progression, defined as an increase in Gleason score from ≤6 to ≥7 or increase in percentage of cores positive for cancer from <34% to ≥34%. Fivefold internal cross-validation was performed to evaluate the area under the receiver operating characteristic curve (AUC). Statistically significant risk factors for progression on biopsy were prostate-specific antigen (odds ratio [OR]: 1.045; 95% confidence interval [CI], 1.028-1.063), percentage of cores positive for cancer on most recent biopsy (OR: 1.401; 95% CI, 1.301-1.508), and history of at least one prior negative biopsy (OR: 0.524; 95% CI, 0.417-0.659). A multivariable predictive model incorporating these factors plus age and number of months since last biopsy achieved an AUC of 72.4%. A combination of readily available clinical measures can stratify patients considering AS prostate biopsy. Risk of progression or upgrade can be estimated and incorporated into clinical practice. The Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator, an online tool, can be used to guide patient decision making regarding follow-up prostate biopsy.


A first insight into the genotypic diversity of Mycobacterium tuberculosis from Rwanda.
Mycobacterium tuberculosis complex (MTC) is the causative agent of tuberculosis (TB). Globally, increasing evidence shows that in M. tuberculosis, transmission varies from strain to strain and that different strains exhibit a range of geographical and host specificities, pathogenicity, and drug susceptibility. Therefore rapid and accurate differentiation of the members of MTC is critical in guiding treatment and public health decisions. We carried out a study at different health units and the National Reference Laboratory in Rwanda identify Mycobacterium tuberculosis complex species prevalent in TB patients in Rwanda. We further characterized the isolates using spoligotyping in order to gain an insight into the strain diversity of drug resistant and susceptible isolates of M. tuberculosis in this setting. A total of 151 isolates from culture positive sputum samples were harvested, heat killed at 80°C for two hours, and then shipped to Makerere University College of Health Sciences, Uganda, for speciation and typing. Species identification was achieved by regions of difference (RD) analysis, while Spoligotyping was done to identify strain types. Region of difference analysis identified all the 151 isolates as M. tuberculosis. Spoligotyping revealed predominance of the T2 family (58.3%, 88/151), with SIT 52 being the most prevalent strain (31.8%, 48/151). Among the 151 isolates, 64 (42.4%) were multidrug resistant (MDR) with 3 cases on mono-resistance. Of 94 retreatment cases, 48 (51.1%) were MDR and of 46 newly presenting cases 14 (30.4%) were MDR. There was a significant difference (p=0.01) in anti-TB drug resistance between new and retreatment cases in the sample. However, there was no significant relationship between HIV serostatus and the two major strain types SIT 52 (p =0.15and SIT 152 (p = 0.41). Mycobacterium tuberculosis is the most prevalent species of Mycobacterium tuberculosis complex in Rwanda, and SIT 52 (T2) the predominant strain. There is significantly more MDR in the retreatment cases but no significant difference was observed by HIV status in relation to any spoligotypes.


Synaptically-competent neurons derived from canine embryonic stem cells by lineage selection with EGF and Noggin.
Pluripotent stem cell lines have been generated in several domestic animal species; however, these lines traditionally show poor self-renewal and differentiation. Using canine embryonic stem cell (cESC) lines previously shown to have sufficient self-renewal capacity and potency, we generated and compared canine neural stem cell (cNSC) lines derived by lineage selection with epidermal growth factor (EGF) or Noggin along the neural default differentiation pathway, or by directed differentiation with retinoic acid (RA)-induced floating sphere assay. Lineage selection produced large populations of SOX2+ neural stem/progenitor cell populations and neuronal derivatives while directed differentiation produced few and improper neuronal derivatives. Primary canine neural lines were generated from fetal tissue and used as a positive control for differentiation and electrophysiology. Differentiation of EGF- and Noggin-directed cNSC lines in N2B27 with low-dose growth factors (BDNF/NT-3 or PDGFαα) produced phenotypes equivalent to primary canine neural cells including 3CB2+ radial progenitors, MOSP+ glia restricted precursors, VIM+/GFAP+ astrocytes, and TUBB3+/MAP2+/NFH+/SYN+ neurons. Conversely, induction with RA and neuronal differentiation produced inadequate putative neurons for further study, even though appropriate neuronal gene expression profiles were observed by RT-PCR (including Nestin, TUBB3, PSD95, STX1A, SYNPR, MAP2). Co-culture of cESC-derived neurons with primary canine fetal cells on canine astrocytes was used to test functional maturity of putative neurons. Canine ESC-derived neurons received functional GABA(A)- and AMPA-receptor mediated synaptic input, but only when co-cultured with primary neurons. This study presents established neural stem/progenitor cell populations and functional neural derivatives in the dog, providing the proof-of-concept required to translate stem cell transplantation strategies into a clinically relevant animal model.


Relationship between visual function and cognitive function in the elderly: A cross-sectional observational study.
It has been suggested that functional visual acuity (VA) testing may be able to measure both the visual performance and cognitive ability needed for driving and help to reduce the number of road traffic accidents. The aim of this study was to investigate the relationship between visual ability and cognitive function in healthy elderly subjects. The study included 34 eyes with a decimal best-corrected visual acuity (VA) ≥1.0 in 34 subjects (16 men, 18 women; mean age 72.7 ± 6.1 [range, 61-83] years) with the same type of monofocal intraocular lens implant. Using the score on the Japanese version of the Mini-Mental State Examination (MMSE) questionnaire, the subjects were divided into a mild cognitive impairment (MCI) group (score <28) and a normal cognition (NC) group (score ≥28). Visual ability was evaluated by functional VA testing. Functional VA was significantly lower in the MCI group (n = 10) than in the NC group (n = 24; P<0.02). There was no significant difference in best-corrected VA between the two groups. High correlations were found between the MMSE score and the logMAR functional VA (r = -0.36, P = 0.04), standard deviation of functional VA (r = -0.39, P = 0.02), and the visual maintenance ratio (r = 0.34, P = 0.048). In summary, despite a good best-corrected VA, deterioration in visual ability was detected in elderly individuals with MCI when measured by the functional VA test. Functional VA could be used to evaluate the integrated visual ability associated with age-related cognitive decline and have applications that help to reduce the disproportionately high rate of road traffic accidents in the elderly.


Analysis of multivariate failure-time data from HIV clinical trials.
We illustrate the use of marginal methods for the analysis of multivariate failure-time data using a large trial in HIV infection in which the composite endpoint of AIDS or death incorporates more than 20 events with varying severity. Multivariate failure-time methods are required to investigate whether treatment delays development of new AIDS events. AIDS events can be grouped and treatment effects estimated using only the first event to occur in each group for each individual. Alternatively, all events can be included by fitting a separate baseline hazard for development of each event, and restricting treatment effects to be common within groups of events. In either case, model-based or minimum-variance estimates of the overall effect of treatment can be constructed. The covariance matrix for the treatment-effect estimates can be used in multiple testing procedures. Results from the Delta trial suggest that combination antiretroviral therapy with AZT plus either ddI or ddC may delay progression to more severe AIDS events compared to AZT monotherapy. These late events are generally untreatable and prophylaxis is not available. Trials are not generally powered to detect treatment effects on individual events making up a composite endpoint, and therefore all analyses are exploratory rather than providing definitive evidence. However, marginal multivariate models provide an easily available approach for modeling the effect of covariates on multiple disease processes, and allow the likely effects of treatment to be presented in a manner which is easily understood. They can be used in a variety of ways to explore different patterns of treatment effects and are also useful for testing multiple hypotheses regarding treatment effects on several different composite endpoints.


Characterization of Nippostrongylus brasiliensis infection in different strains of mice.
Five mouse strains, CBA/J, BALB/c, C3H/HeJ, A/J, and C57Bl/6J-bg-bg, all showed similar expulsion kinetics for Nippostrongylus brasiliensis (infective dose = 500 L3). Typically, parasite recovery was maximal on day 2 in the lungs and by day 4 in the small intestine. Few worms (less than 5% infective dose) were recovered on day 14 in all strains. These same mouse strains exhibited immune depression on day 5 of infection with mesenteric lymph node cells (MLN) showing reduced (10-30% normal) IgM, IgG, and IgA responses against heterologous antigen. The intestinal mast cell numbers and tissue histamine levels were examined in CBA/J mice. Mast cell numbers increased (normal = less than 1/villous crypt unit; VCU) from day 5 and peaked on day 12 (greater than 15/VCU). Intestinal histamine levels did not completely correlate with mast cell numbers with maximum concentrations (240 +/- 73 ng/g, 2-fold over normal) reached by day 8. Histamine concentrations in the intestine returned to normal levels by day 20.


Influence of a Nigerian honey on CYP3A4 biotransformation of quinine in healthy volunteers.
Some studies, howbeit with conflicting reports, have suggested that consumption of honey has a potential to modulate drug metabolizing enzymes which may result in a honey-drug interaction. Numerous studies have established that honey varies in composition, influenced by the dominant floral, processing and environmental factors. Thus, variation in honey composition may be a contributing factor to the controversial results obtained. No previous drug interaction study has been carried out with any honey from Africa. CYP 3A4 is an important enzyme in drug metabolism studies as it is involved in the metabolism of over 50% of drugs in clinical use and quinine remains very relevant in malaria treatment in the tropics, and we therefore determined whether there is potential drug interaction between a Nigerian honey and quinine, a drug whose metabolism to 3-hydroxyquinine is mediated majorly by CYP3A4. In a three-phase randomized crossover study with a washout period of 2 weeks between each treatment phase, ten (10) healthy volunteers received quinine sulphate tablet (600 mg single dose) alone (phase 1) or after administration of 10 ml of honey (Phase 2) and 20 mL of honey (Phase 3) twice daily for seven (7) days. Blood samples were collected at the 16th hour post-quinine administration in each phase, and quinine and its major metabolite, 3-hydroxyquinine, were analysed using a validated HPLC method. After scheduled doses of honey, the mean metabolic ratios of quinine (3-hydroxyquinine/quinine) increased by 24·4% (with 10 mL of honey) and reduced by 23·9% (with 20 mL of honey) when compared to baseline. These magnitudes of alteration in the mean metabolic ratios were not significant (P > 0·05; Friedman test). The geometric mean (95% CI) for the metabolic ratio of quinine before and after honey intake at the two dose levels studied was 0·82 (0·54, 1·23) and 1·29 (0·96, 1·72), respectively, and were also not significant (P = 0·296 and 0·081 respectively; Student's t-test). This is a pioneer study on the effect of Nigerian/African honey on quinine metabolism. The findings indicated that low and high doses of honey did not significantly affect metabolism of quinine to 3-hydroxyquinine. This suggests that CYP3A4 activity is not significantly altered following low or high dose of honey, as CYP3A4 has been reported to be responsible for the conversion of quinine to 3-hydroxyquinine. In conclusion, the outcome of this study suggests that there may be no potential significant metabolic interaction between Nigerian honey and quinine administration.


Students' experiences of implementing clinical skills in the real world of practice.
To examine the factors that impact on students' implementation of clinical skills in the practice setting. This was a part of a larger exploration into the role of the Clinical Skills Laboratory in preparing student nurses for clinical practice. It is already known that students can experience reality shock on clinical placement and that staff support is crucial for their adaptation to the environment. This process is similar to socialisation theory whereby the newcomer adapts to the workplace. A multiple case study design (n = 5) was used. Data were collected using semi-structured interviews (n = 43) and non-participant observation of students implementing skills in clinical practice. Findings revealed the factors that could facilitate students' implementation of clinical skills were as follows: provision of learning opportunities, staff support and supervision, and students' confidence. Factors that hindered students were reality shock, 'the gap' in how skills were taught in the higher education institutions and the clinical setting, and missed learning opportunities. Support from peers in the clinical area and having previous experience of working as a health care assistant, or similar, were the factors that could either positively or negatively impact on students. Students need to be adequately prepared for the real-life clinical environment. Understanding, through socialisation theory, how students adapt to the workplace can facilitate this process. Facilitating students' learning includes supporting them, developing their confidence and ensuring that they have prior exposure to undertaking clinical skills. Staff working with students in clinical practice can help facilitate students' learning and implementing of clinical skills through an understanding of how students adapt and 'fit in' to their working environment.


Twists and turns: a tale of two shikimate-pathway enzymes.
We are studying two enzymes from the shikimate pathway, dehydroquinate synthase (DHQS) and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Both enzymes have been the subject of numerous studies to elucidate their reaction mechanisms. Crystal structures of DHQS and EPSPS in the presence and absence of substrates, cofactors and/or inhibitors are now available. These structures reveal movements of domains, rearrangements of loops and changes in side-chain positions necessary for the formation of a catalytically competent active site. The potential for using complementary small-angle X-ray scattering (SAXS) studies to confirm the presence of these structural differences in solution has also been explored. Comparative analysis of crystal structures, in the presence and absence of ligands, has revealed structural features critical for substrate-binding and catalysis. We have also analysed these structures by generating GRID energy maps to detect favourable binding sites. The combination of X-ray crystallography, SAXS and computational techniques provides an enhanced analysis of structural features important for the function of these complex enzymes.


Mental Illness and BRCA1/2 Genetic Testing Intention Among Multiethnic Women Undergoing Screening Mammography.
To examine associations between patient-reported mental illness diagnosis and symptoms and BRCA1/2 genetic testing intention among women undergoing screening mammography. 100 multiethnic women of lower socioeconomic status who were undergoing mammography screening and met family history criteria for BRCA1/2 genetic testing. Descriptive and bivariate nonparametric statistics and multivariate logistic regression were used to examine associations between mental illness and genetic testing intention. Variables were anxiety, depression, patient-reported mental illness diagnosis and symptoms, and testing intention. Prevalence rates of mental illness symptoms were 36% for clinically significant depression and 36% for anxiety. Although 76% of participants intended to undergo genetic testing, only 5% had completed testing. History of mental illness and elevated levels of anxiety and depressive symptoms were positively correlated with testing intention in the bivariate analysis. In multivariate analysis, only younger age and less education were associated with testing intention. Future studies should address psychosocial needs and other competing barriers at the patient, provider, and healthcare system levels to increase access to BRCA1/2 genetic testing among multiethnic women.


Functional characterization and metal ion specificity of the metal-citrate complex transporter from Streptomyces coelicolor.
Secondary transporters of citrate in complex with metal ions belong to the bacterial CitMHS family, about which little is known. The transport of metal-citrate complexes in Streptomyces coelicolor has been investigated. The best cofactor for citrate uptake in Streptomyces coelicolor is Fe(3+), but uptake was also noted for Ca(2+), Pb(2+), Ba(2+), and Mn(2+). Uptake was not observed with the Mg(2+), Ni(2+), or Co(2+) cofactor. The transportation of iron- and calcium-citrate makes these systems unique among the CitMHS family members reported to date. No complementary uptake akin to that observed for the CitH (Ca(2+), Ba(2+), Sr(2+)) and CitM (Mg(2+), Ni(2+), Mn(2+), Co(2+), Zn(2+)) systems of Bacillus subtilis was noted. Competitive experiments using EGTA confirmed that metal-citrate complex formation promoted citrate uptake. Uptake of free citrate was not observed. The open reading frame postulated as being responsible for the metal-citrate transport observed in Streptomyces coelicolor was cloned and overexpressed in Escherichia coli strains with the primary Fe(3+)-citrate transport system (fecABCDE) removed. Functional expression was successful, with uptake of Ca(2+)-citrate, Fe(3+)-citrate, and Pb(2+)-citrate observed. No free-citrate transport was observed in IPTG (isopropyl-beta-d-thiogalactopyranoside)-induced or -uninduced E. coli. Metabolism of the Fe(3+)-citrate and Ca(2+)-citrate complexes, but not the Pb(2+)-citrate complex, was observed. Rationalization is based on the difference in metal-complex coordination upon binding of the metal by citrate.


Risks and benefits of giving early Aspirin within 6 hours of CABG: A retrospective analysis.
Antiplatelet drugs are frequently used after coronary artery bypass graft (CABG) surgery to prevent venous graft occlusion. The fear of bleeding complications prevents them to be given early post operatively, which is the time when antiplatelets use confers maximum benefit. Our objective was to determine the effect and influence of early aspirin therapy on fatal and nonfatal bleeding complications and blood requirements after coronary bypass surgery (CABG). The patients who only underwent coronary artery bypass surgery for the first time in the past three years and did not have any bleeding diathesis were retrospectively analyzed from the cardiac surgery database of CPEIC Multan. The patients either received aspirin within six hours of CABG or had it given after 12 hours. The patients were analyzed for mean blood loss and number of blood units transfused. SPSS was used for statistical analysis. P value < 0.05 was considered significant. Total 281 patients received aspirin within six hours while 326 patients did not. Mean blood loss in early aspirin group was 727ml as compared to 767ml in the other group (p value 0.74). The median number of blood units transfused was 2 (p value 0.98). Our results did not show any statistical difference in both the groups. Aspirin can safely be given early after CABG without the fear of bleeding complications thus conferring the advantage of increased graft patency.


Prostate cancer detection on transrectal ultrasonography-guided random biopsy despite negative real-time magnetic resonance imaging/ultrasonography fusion-guided targeted biopsy: reasons for targeted biopsy failure.
To examine the value of additional transrectal ultrasonography (TRUS)-guided random biopsy (RB) in patients with negative magnetic resonance imaging (MRI)/ultrasonography (US) fusion-guided targeted biopsy (TB) and to identify possible reasons for TB failure. We conducted a subgroup analysis of 61 men with prostate cancer (PCa) detected by 10-core RB but with a negative TB, from a cohort of 408 men with suspicious multiparametric magnetic resonance imaging (mpMRI) between January 2012 and January 2015. A consensus re-reading of mpMRI results (using Prostate Imaging Reporting and Data System [PI-RADS] versions 1 and 2) for each suspicious lesion was performed, with the image reader blinded to the biopsy results, followed by an unblinded anatomical correlation of the lesion on mpMRI to the biopsy result. The potential reasons for TB failure were estimated for each lesion. We defined clinically significant PCa according to the Epstein criteria and stratified patients into risk groups according to the European Association of Urology guidelines. Our analysis showed that RB detected significant PCa in 64% of patients (39/61) and intermediate-/high-risk PCa in 57% of patients (35/61). The initial mpMRI reading identified 90 suspicious lesions in the cohort. Blinded consensus re-reading of the mpMRI led to PI-RADS score downgrading of 45 lesions (50%) and upgrading of 13 lesions (14%); thus, negative TB could be explained by falsely high initial PI-RADS scores for 32 lesions (34%) and sampling of the target lesion by RB in the corresponding anatomical site for 36 out of 90 lesions (40%) in 35 of 61 patients (57%). Sampling of the target lesion by RB was most likely for lesions with PI-RADS scores of 4/5 and Gleason scores (GS) of ≥7. A total of 70 PCa lesions (67% with GS 6) in 44 patients (72%) were sampled from prostatic sites with no abnormalities on mpMRI. In cases of TB failure, RB still detected a high rate of significant PCa. The main reason for a negative TB was a TB error, compensated for by positive sampling of the target lesion by the additional RB, and the second reason for TB failure was a falsely high initial PI-RADS score. The challenges that arise for both MRI diagnostics and prostate lesion sampling are evident in our data and support the integration of RB into the TB workflow.


Restenosis after balloon angioplasty. A practical proliferative model in porcine coronary arteries.
A model of proliferative human restenosis was developed in domestic pigs by using deep injury to the coronary arterial media. Metal wire coils were delivered percutaneously to the coronary arteries of 11 pigs with an oversized, high-pressure (14 atm) balloon and were left in place for times ranging from 28 to 70 days. During placement, the balloon expanded the coils and delivered them securely within the arterial lumen. Light microscopic examination of the vessels confirmed fracture of the internal elastic lamina by the coil. An extensive proliferative response occurred in 10 of the 11 pigs and was associated with a luminal area narrowing of at least 50% in all but one pig. The histopathologic features of the proliferative response were identical to those observed in human cases of restenosis after angioplasty. Immunohistochemical studies confirmed the prominence of smooth muscle cells in the proliferative tissue. A similar response was obtained in two of five porcine coronary arteries in which balloon inflation only was performed, without coil implant. This model is practical and inexpensive and closely mimics the proliferative portion of human restenosis both grossly and microscopically. Thus, it may be useful for understanding human restenosis and for testing therapies aimed at preventing restenosis after balloon angioplasty or other coronary interventional procedures.


Increased vascular reactivity to Bay K 8644 in genetic hypertension.
These experiments compared potential-operated calcium channel function in smooth muscle from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Carotid artery strips from adult male SHRSP and WKY rats were suspended in tissue baths for isometric force recording. Contractile force was expressed as percent of response to 100 mmol/l KCl. Vascular strips from SHRSP were more sensitive to KCl (ED50 = 25 mmol/l) compared to strips from WKY rats (ED50 = 37 mmol/l). The calcium channel agonist Bay K 8644 (2.8 x 10(-10) to 2.8 x 10(-7) mol/l) produced tonic contractions in carotid artery strips from SHRSP (34% of the contractile response to 100 mmol/l KCl) but not in those from WKY rats. Incubation of vascular strips in 1.8 or 6 x 10(-10) mmols/l norepinephrine did not alter the maximal contractile response to Bay K 8644 in either strain of rats. In 12 mmol/l KCl, the maximal contractile response to Bay K 8644 was increased in both SHRSP (71%) and WKY rats (25%). In 18 mmol/l KCl, maximal contractile responses to Bay K 8644 in the two strains were similar (SHRSP = 73%, WKY = 76%). Removal of the endothelium did not significantly affect contractile responses to Bay K 8644 in either strain of rats. There were no differences in contractile responses to the calcium ionophore A23187 or in nifedipine-induced relaxation of potassium-activated vessels between carotid arteries from SHRSP and WKY rats. In summary, these results suggest that a difference in voltage-operated calcium channel function may underlie the increased sensitivity of SHRSP vascular smooth muscle to depolarizing stimuli.


Why women do not use contraceptives: Exploring the role of male out-migration.
Contextual understanding of reasons for non-use of contraceptives is key to devising family planning (FP) strategies. This study aimed to understand the reasons for non-use of contraceptives among women in the context of male out-migration. Focus Group Discussions (FGDs) were conducted in two high male out-migration districts in Bihar, namely Nawada and Gopalganj. Twenty-five FGDs were conducted with currently married women with migrant husbands, currently married men and Accredited Social Health Activists (ASHAs) during April-June 2019. Data were analysed by using a thematic approach through Atlas.ti-6.2. The reasons for contraceptive non-use in areas with high male out-migration were complex, as this included barriers to contraceptive use unique to high-migration areas and reasons commonly found in other rural settings. Non-use of contraceptives among women with migrant husbands was mostly driven by lack of contraceptive preparedness before husband's arrival, inability to procure contraceptives due to inaccessibility to health facilities and stigma to procure when husband was away. Other migration environment related factors included low ASHA outreach, myths and side effects of contraceptives, community fertility norms and poor spousal communications around FP. The reasons for non-use of contraceptives are multifaceted, complex and interlinked. Exploration of these reasons in migration context suggest that FP programs in migration affected areas need to address a range of barriers to contraceptive use at multiple levels.


Pregnant women's concerns and antenatal care during COVID-19 lock-down of the Danish society.
Pandemics are known to cause stress and anxiety in pregnant women. During the coronavirus disease 2019 (COVID-19) lockdown of the Danish society, pregnant women were considered to be at increased risk, and access to antenatal care changed. On 8 April 2020A, a questionnaire was sent to 332 pregnant women previously sampled by general practitioners in two Danish regions. The women were contacted via secured e-mail (e-Boks), and questionnaires were returned until 6 May. The questionnaire was returned by 257 women (77%). More than half believed that they were at a high risk of infection with COVID-19, and a third of the women were concerned about the risk of serious disease - especially for their unborn child. Almost 90% isolated at home most of the time. The majority were worried about possible consequences of the pandemic for antenatal care, but very few had actually missed a scheduled preventive consultation with their general practitioner, and only 15% had missed an appointment with their midwife. The majority of the women preferred normal consultations and found no added safety in shifting the consultation from the normal clinical setting. The COVID-19 pandemic and lockdown have had a major impact on Danish pregnant women. Even so, concerns were more focused on access to care than on the risk of COVID-19 infection. Contacts with the antenatal healthcare system have only been moderately affected. TRYG Foundation and KEU, Region Copenhagen. not relevant.


Hydrophilic electrospun polyurethane nanofiber matrices for hMSC culture in a microfluidic cell chip.
Mimicking cellular microenvironments by MEMS technology is one of the emerging research areas. Integrated biomimetic systems with nanofiber polymer networks and microfluidic chips were fabricated and cellular behaviors were observed by changing surface characteristics of nanofibers and flow rates of microchannels. Modification of polyurethane nanofiber surfaces were achieved by grafting acrylic acid with plasma treatment and these nanofiber matrices were employed in a poly(dimethylsiloxane) based microfluidic chip. The surface characteristics of both electrospun nanofiber matrices was evaluated by measuring contact angle, porosity, and chemical structure using attenuated total reflection-Fourier transform infrared spectrometry. After modification, a terminal carboxyl group formed on the nanofiber surface and the wettability increased significantly. Human MSCs were seeded on the nanofiber matrices and a morphological investigation with actin filament staining and scanning electron microscopy was performed. A proliferation test by WST-1 and Live/Dead assay were performed to investigate the cell culture environment. It was observed that the cells on the AA-grafted nanofibers spread and proliferate compared to untreated nanofibers. It has also shown that flow rates in the microchannels played an important role for cell proliferation (Sim et al., Lab Chip 2007;7:1775-1782). Integration of nanofiber matrices into the microchannels provides the useful tools for mimicking cellular microenvironments and elucidating basic questions of cell and ECM assembly and interactions.


The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention.
Almost one fifth of malignancies worldwide and about one quarter in China are associated with viral or bacterial infections, mediating an inflammatory environment in the tumor. Hepatitis viruses (B and C), Epstein Barr Virus (EBV), and helicobacter pylori have been linked to liver, gastric, and nasopharyngeal cancer. The context of infection and chronic inflammation in these cancers may provide an opportunity for therapeutic intervention based on the role of immune checkpoint pathways, which are an important defense mechanism of many cancers against a tumor-directed immune response. Specifically, the expression of the inhibitory receptor PD-1 on the surface of activated T cells has been associated with T cell exhaustion in inflammatory and tumor environments. Furthermore, tumors have been found to over-express the PD-1 ligand B7-H1. Recent therapeutic successes with monoclonal antibodies directed against both B7-H1 and PD-1 in patients with advanced melanoma, renal cell cancer (RCC), and non-small cell cancer, along with the prominent role of this immune checkpoint axis in the inflammatory tumor context, suggest that B7-H1/PD-1 blockade may be particularly beneficial in cancers associated with infections and inflammation.


Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet-induced obese mice is associated with gut microbial changes and reduction in obesity.
To investigate the functional effects of probiotic treatment on the gut microbiota, as well as liver and adipose gene expression in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce obesity, and then randomized to receive HFD+probiotic (Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, n = 9) or HFD+placebo (n = 9) for another 10 weeks. Normal diet (ND) fed mice (n = 9) served as non-obese controls. Diet-induced obese mice treated with probiotics showed reduced body weight gain and fat accumulation as well as lowered plasma insulin, leptin, total-cholesterol and liver toxicity biomarkers. A total of 151,061 pyrosequencing reads for fecal microbiota were analyzed with a mean of 6,564, 5,274 and 4,464 reads for the ND, HFD+placebo and HFD+probiotic groups, respectively. Gut microbiota species were shared among the experimental groups despite the different diets and treatments. The diversity of the gut microbiota and its composition were significantly altered in the diet-induced obese mice and after probiotic treatment. We observed concurrent transcriptional changes in adipose tissue and the liver. In adipose tissue, pro-inflammatory genes (TNFα, IL6, IL1β and MCP1) were down-regulated in mice receiving probiotic treatment. In the liver, fatty acid oxidation-related genes (PGC1α, CPT1, CPT2 and ACOX1) were up-regulated in mice receiving probiotic treatment. The gut microbiota of diet-induced obese mice appears to be modulated in mice receiving probiotic treatment. Probiotic treatment might reduce diet-induced obesity and modulate genes associated with metabolism and inflammation in the liver and adipose tissue.


Operando soft X-ray emission spectroscopy of the Fe2O3 anode to observe the conversion reaction.
Drastic electronic-structure changes in an Fe2O3 thin film anode for a Li-ion battery during discharge (lithiation) and charge (delithiation) processes were observed using operando Fe 2p soft X-ray emission spectroscopy (XES). The conversion reaction forming metallic iron due to the lithiation reaction was confirmed by operando XES in combination with the analysis using full-multiplet calculation. The valence of Fe at the open-circuit voltage (OCV) before the second cycle was not Fe3+, but Fe2+ with a weak p-d hybridization, suggesting a considerable irreversibility upon the first discharge-charge cycle and a weakened Fe-O bond after the first cycle. Moreover, we revealed that the Fe 3d electronic-structure change during the second cycle was to some extent reversible as Fe2+ (2.7 V vs. Li/Li+: open circuit voltage) → Fe0 (0.1 V vs. Li/Li+: discharged) → Fe(2+δ)+ (3.0 V vs. Li/Li+: charged). This operando Fe 2p XES in combination with the full-multiplet calculation provides detailed information for redox chemistry during a discharge-charge operation that cannot be obtained by other methods such as crystal-structure and morphology analyses. XES is thus very powerful for investigating the origin and limitation of the lithiation function of anodes involving conversion reactions.


In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus.
A total of 100 herpes simplex viruses isolated from lesions not responding to acyclovir (ACV) therapy were recovered from 51 patients infected with human immunodeficiency virus. In vitro analysis of these isolates included testing their susceptibility to ACV and determining their thymidine kinase (TK) phenotypes. Of the 100 isolates evaluated, 23 were ACV sensitive and 77 were ACV resistant. Seventy-four of these ACV-resistant isolates were of the TK-deficient or low-TK-producer phenotype and three were of the TK-altered phenotype. The TKs isolates that represented each of the different autoradiographic phenotypes were further characterized by enzyme kinetics. The ability of selected isolates to cause disease in vivo was evaluated by using several mouse virulence models. Cutaneous virulence in normal and immunocompromised mice was evaluated, and neurovirulence in normal mice was determined. Latent infections were assayed by the cocultivation of trigeminal ganglia recovered from mice that had survived acute infection. These reactivated viruses were evaluated in vitro and compared with the original infecting isolate. The mechanisms of resistance and pathogenicity of these herpes simplex virus isolates recovered from patients positive for human immunodeficiency virus are similar to those reported for isolates recovered from normal and immunocompromised patients without AIDS.


Time-reversal symmetry breaking superconductivity in the coexistence phase with magnetism in Fe pnictides.
We argue that superconductivity in the coexistence region with spin-density-wave (SDW) order in weakly doped Fe pnictides erdiffers qualitatively from the ordinary s(+-) state outside the coexistence region as it develops an additional gap component which is a mixture of intrapocket singlet (s(++)) and interpocket spin-triplet pairings (the t state). The coupling constant for the t channel is proportional to the SDW order and involves interactions that do not contribute to superconductivity outside of the SDW region. We argue that the s(+-)- and t-type superconducting orders coexist at low temperatures, and the relative phase between the two is, in general, different from 0 or π, manifesting explicitly the breaking of the time-reversal symmetry promoted by long-range SDW order. We argue that time reversal may get broken even before true superconductivity develops.


Meta-analysis of parental protection of children from tobacco smoke exposure.
Worldwide, roughly 40% of children are exposed to the damaging and sometimes deadly effects of tobacco smoke. Interventions aimed at reducing child tobacco smoke exposure (TSE) have shown mixed results. The objective of this study was to perform a systematic review and meta-analysis to quantify effects of interventions aimed at decreasing child TSE. Data sources included Medline, PubMed, Web of Science, PsycNet, and Embase. Controlled trials that included parents of young children were selected. Two reviewers extracted TSE data, as assessed by parentally-reported exposure or protection (PREP) and biomarkers. Risk ratios and differences were calculated by using the DerSimonian and Laird random-effects model. Exploratory subgroup analyses were performed. Thirty studies were included. Improvements were observed from baseline to follow-up for parentally-reported and biomarker data in most intervention and control groups. Interventions demonstrated evidence of small benefit to intervention participants at follow-up (PREP: 17 studies, n = 6820, relative risk 1.12, confidence interval [CI] 1.07 to 1.18], P < .0001). Seven percent more children were protected in intervention groups relative to control groups. Intervention parents smoked fewer cigarettes around children at follow-up than did control parents (P = .03). Biomarkers (13 studies, n = 2601) at follow-up suggested lower child exposure among intervention participants (RD -0.05, CI -0.13 to 0.03, P = .20). Interventions to prevent child TSE are moderately beneficial at the individual level. Widespread child TSE suggests potential for significant population impact. More research is needed to improve intervention effectiveness and child TSE measurement.


Management of Axillary Web Syndrome after Breast Cancer: Evidence-Based Practice.
Axillary web syndrome is characterized as a physical-functional complication that impacts the quality of life of women who have undergone treatment for breast cancer. The present study aims to verify the physiotherapy treatment available for axillary web syndrome after surgery for breast cancer in the context of evidence-based practice. The selection criteria included papers discussing treatment protocols used for axillary web syndrome after treatment for breast cancer. The search was performed in the MEDLINE, Scopus, PEDro and LILACS databases using the terms axillary web syndrome, lymphadenectomy and breast cancer, focusing on women with a previous diagnosis of breast cancer who underwent surgery with lymphadenectomy as part of their treatment. From the 262 studies found, 4 articles that used physiotherapy treatment were selected. The physiotherapy treatment was based on lymphatic drainage, tissue mobilization, stretching and strengthening. The four selected articles had the same outcome: improvement in arm pain and shoulder function and/or dissipation of the axillary cord. Although axillary web syndrome seems to be as frequent and detrimental as other morbidities after cancer treatment, there are few studies on this subject. The publications are even scarcer when considering studies with an interventional approach. Randomized controlled trials are necessary to support the rehabilitation resources for axillary web syndrome.


Non-invasive surface-stripping for epifluorescence small animal imaging.
Non-invasive near-infrared fluorescence (NIRF) imaging is a powerful tool to study pathophysiology in a wide variety of animal disease models including brain diseases. However, especially in NIRF imaging of the brain or other deeper laying target sites, background fluorescence emitted from the scalp or superficial blood vessels can impede the detection of fluorescence in deeper tissue. Here, we introduce an effective method to reduce the impact of fluorescence from superficial layers. The approach uses excitation light at two different wavelengths generating two images with different depth sensitivities followed by an adapted subtraction algorithm. This technique leads to significant enhancement of the contrast and the detectability of fluorochromes located in deep tissue layers in tissue simulating phantoms and murine models with stroke.


Multiuser CSK scheme for indoor visible light communications.
Color Shift Keying (CSK) is a new modulation scheme for visible light communication systems using RGB LEDs which has been standardized in the PHY III level of the IEEE 802.15.7. This paper proposes some modifications so as to include multiuser capabilities provided by a time-based multiplexing, with the modulation constellation symbols being adapted to encode data with the luminux powers of the red, green and blue color bands respectively. This is achieved by employing a simple and low-complexity time-based pulse signals structure to separate the users' data symbols, while a three-dimensional signal constellation design is merged to improve data throughput. Numerical simulations are carried out to assess the performance of this novel architecture. The statistical properties of the transmitted RGB signals ensure dimming capabilities and that the illumination function is unaffected by flickering.


Local food prices and their associations with children's weight and food security.
Both obesity and food insecurity are important public health problems facing young children in the United States. A lack of affordable, healthy foods is one of the neighborhood factors presumed to underlie both food insecurity and obesity among children. We examine associations between local food prices and children's BMI, weight, and food security outcomes. We linked data from the Early Childhood Longitudinal Study-Birth Cohort, a nationally representative study of children from infancy to age 5, to local food price data from the Council for Community and Economic Research (C2ER) Cost-of-Living Index (n = 11,700 observations). Using ordinary least squares (OLS), linear probability, and within-child fixed effects (FE) models, we exploit the variability in food price data over time and among children who move residences focusing on a subsample of households under 300% of the Federal Poverty Level. Results from ordinary least squares and FE models indicate that higher-priced fruits and vegetables are associated with higher child BMI, and this relationship is driven by the prices of fresh (versus frozen or canned) fruits and vegetables. In the FE models, higher-priced soft drinks are associated with a lower likelihood of being overweight, and surprisingly, higher fast food prices are associated with a greater likelihood of being overweight. Policies that reduce the costs of fresh fruits and vegetables may be effective in promoting healthy weight outcomes among young children.


Prevention of parenteral nutrition-associated liver disease: role of omega-3 fish oil.
Parenteral nutrition-associated liver disease (PNALD) is the most severe complication of long-term parenteral nutrition. Its cause remains unclear, although recent studies suggest that the omega-6 polyunsaturated fatty acids in plant oil-based lipid emulsions and the associated phytosterols contribute to the development of hepatotoxicity. In contrast, fish oil-based lipid emulsions are composed mainly of omega-3 polyunsaturated fatty acids and are hypothesized to be hepatoprotective. This review will discuss fish oil-based lipid emulsions in the prevention of PNALD. In several animal models of PNALD, the use of an intravenous fish oil-based lipid emulsion improved parenteral nutrition-associated cholestasis without resultant essential fatty acid deficiency or growth impairment. Following these results and preliminary human data, an open trial for compassionate use was initiated, followed by a randomized controlled trial to evaluate the current management of pediatric PNALD. To date, at the author's institution, more than 130 children with PNALD have been treated with Omegaven, a fish oil-based emulsion, with improved liver function among most patients. PNALD remains the most severe complication of long-term parenteral nutrition with an unclear pathophysiology. However, the use of a fish oil-based emulsion appears efficacious and hepatoprotective.


High Photostability in Nonconventional Coumarins with Far-Red/NIR Emission through Azetidinyl Substitution.
Replacement of electron-donating N,N-dialkyl groups with three- or four-membered cyclic amines (e.g., aziridine and azetidine, respectively) has been described as a promising approach to improve some of the drawbacks of conventional fluorophores, including low fluorescent quantum yields (ΦF) in polar solvents. In this work, we have explored the influence of azetidinyl substitution on nonconventional coumarin-based COUPY dyes. Two azetidine-containing scaffolds were first synthesized in four linear synthetic steps and easily transformed into far-red/NIR-emitting fluorophores through N-alkylation of the pyridine moiety. Azetidine introduction in COUPY dyes resulted in enlarged Stokes' shifts with respect to the N,N-dialkylamino-containing parent dyes, but the ΦF were not significantly modified in aqueous media, which is in contrast with previously reported observations in other fluorophores. However, azetidinyl substitution led to an unprecedented improvement in the photostability of COUPY dyes, and high cell permeability was retained since the fluorophores accumulated selectively in mitochondria and nucleoli of HeLa cells. Overall, our results provide valuable insights for the design and optimization of novel fluorophores operating in the far-red/NIR region, since we have demonstrated that three important parameters (Stokes' shifts, ΦF, and photostability) cannot be always simultaneously addressed by simply replacing a N,N-dialkylamino group with azetidine, at least in nonconventional coumarin-based fluorophores.


An inexpensive device for non-invasive electroretinography in small aquatic vertebrates.
Electroretinographic (ERG) method records a sum field potential of the retina in response to light. It mainly arises in the outer retina and is used as a non-invasive measure in both animal experiments and the clinic. Since it is a comprehensive method to assess outer retinal function, it is becoming increasingly useful in genetic studies of vision. Here we present a simple in-house built setup to measure ERGs of aquatic vertebrates. We have used this setup to efficiently and reliably measure intact larvae of zebrafish (Danio rerio), Medaka fish (Oryzias latipes), and Xenopus laevis tadpoles. By slight modification of the setup, we were also able to measure adult zebrafish and Medaka, demonstrating the general versatility of the setup. We picked these organisms since they are increasingly used to study visual function with genetic means. This setup is easily built and will be particularly useful for laboratories setting up ERG measurements as a complement to their genetic studies.


Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.
It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.


Evolving Models and Ongoing Challenges for HIV Preexposure Prophylaxis Implementation in the United States.
The use of preexposure prophylaxis (PrEP) for HIV prevention was approved by the Food and Drug Administration in 2012, but delivery to at-risk persons has lagged. This critical review analyzes the current state of PrEP implementation in the United States, by reviewing barriers and innovative solutions to enhance PrEP access and uptake. Clinical care settings, public health programs, and community-based organizations (CBOs). Critical review of recent peer-reviewed literature. More than 100 papers were reviewed. PrEP is currently provided in diverse settings. Care models include sexually transmitted disease clinics, community health centers, CBOs, pharmacies, and private primary care providers (PCPs). Sexually transmitted disease clinics have staff trained in sexual health counseling and are linked to public health programs (eg, partner notification services), whereas PCPs and community health centers may be less comfortable counseling and feel time-constrained in managing PrEP. However, PCPs may be ideal PrEP providers, given their long-term relationships with patients, integrating PrEP into routine care. Collaborations with CBOs can expand PrEP care through adherence support and insurance navigation. Pharmacies can deliver PrEP, given their experience with medication dispensing and counseling, and may be more accessible for some patients, but to address other health concerns, liaisons with PCPs may be needed. PrEP implementation in the United States is moving forward with the development of diverse models of delivery. Optimal scale-up will require learning about the best features of each model and providing choices to consumers that enhance engagement and uptake.


Biologics and chronic obstructive pulmonary disease.
The presence of airway inflammation in patients with chronic obstructive pulmonary disease (COPD) provides a rationale for biological agents targeting specific inflammatory pathways. This approach has been strikingly effective in patients with other chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and asthma. However, there are important and unresolved challenges in COPD, including our incomplete understanding of heterogeneity of the lower airway inflammatory response and how these contribute to the clinical expression of disease. As a result, progress has been slow, and there have been many failures. One notable exception is the targeting of eosinophilic airway inflammation with anti-IL-5, which has an acknowledged and important role in the treatment of severe eosinophilic asthma. Recent phase III studies have shown a reduction in exacerbations of around 20% in patients with COPD and clear evidence of a blood eosinophil count-dependent beneficial effect. The demonstration of clinical efficacy linked to a clinically accessible biomarker raises the possibility of precision biomarker-directed use of biological agents in patients with COPD. The hope is that this will be an exemplar for the future development of biological agents in patients with COPD.


Attenuation of Colitis by Lactobacillus casei BL23 Is Dependent on the Dairy Delivery Matrix.
The role of the food delivery matrix in probiotic performance in the intestine is not well understood. Because probiotics are often provided to consumers in dairy products, we investigated the contributions of milk to the health-benefiting performance of Lactobacillus casei BL23 in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis. L. casei BL23 protected against the development of colitis when ingested in milk but not in a nutrient-free buffer simulating consumption as a nutritional supplement. Consumption of (acidified) milk alone also provided some protection against weight loss and intestinal inflammation but was not as effective as L. casei and milk in combination. In contrast, L. casei mutants deficient in DltD (lipoteichoic acid d-alanine transfer protein) or RecA (recombinase A) were unable to protect against DSS-induced colitis, even when consumed in the presence of milk. Mice fed either L. casei or milk contained reduced quantities of colonic proinflammatory cytokines, indicating that the L. casei DltD(-) and RecA(-) mutants as well as L. casei BL23 in nutrient-free buffer were effective at modulating immune responses. However, there was not a direct correlation between colitis and quantities of these cytokines at the time of sacrifice. Identification of the cecal microbiota by 16S rRNA gene sequencing showed that L. casei in milk enriched for Comamonadaceae and Bifidobacteriaceae; however, the consumption of neither L. casei nor milk resulted in the restoration of the microbiota to resemble that of healthy animals. These findings strongly indicate that probiotic strain efficacy can be influenced by the food/supplement delivery matrix.


Influence of gas stunning and halal slaughter (no stunning) on rabbits welfare indicators and meat quality.
This study assessed the effect of gas stunning which has not been conducted until now in comparison with slaughter without stunning on the welfare and meat quality of rabbits. Eighty male New Zealand White rabbits were divided into two groups of 40 animals and subjected to either halal slaughter without stunning (HS) or gas stunning using 61.4% CO2, 20.3% oxygen and 18.3 % nitrogen (GS). Analysis of the sticking blood revealed that both slaughter procedures caused a substantial increase in the levels of catecholamines, hypercalcemia, hyperglycemia, lactic acidemia and an increase in enzyme activities. The ultimate pH of the Longissimus lumborum muscle did not differ between treatments. GS exhibited higher lightness and cooking loss, and lower glycogen and MFI than HS. This indicates that both GS and HS can be significant stressors although the amount of stress may be below the threshold to negatively affect rabbit meat quality.


Response to early drought stress and identification of QTLs controlling biomass production under drought in pearl millet.
Pearl millet plays a major role in food security in arid and semi-arid areas of Africa and India. However, it lags behind the other cereal crops in terms of genetic improvement. The recent sequencing of its genome opens the way to the use of modern genomic tools for breeding. Our study aimed at identifying genetic components involved in early drought stress tolerance as a first step toward the development of improved pearl millet varieties or hybrids. A panel of 188 inbred lines from West Africa was phenotyped under early drought stress and well-irrigated conditions. We found a strong impact of drought stress on yield components. This impact was variable between inbred lines. We then performed an association analysis with a total of 392,493 SNPs identified using Genotyping-by-Sequencing (GBS). Correcting for genetic relatedness, genome wide association study identified QTLs for biomass production in early drought stress conditions and for stay-green trait. In particular, genes involved in the sirohaem and wax biosynthesis pathways were found to co-locate with two of these QTLs. Our results might contribute to breed pearl millet lines with improved yield under drought stress.


The prevalence of peripheral and central hearing impairment and its relation to cognition in older adults.
Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline.


The Relationship Between Multimorbidity and Types of Chronic Diseases and Self-Rated Memory.
This study explores the impact of multimorbidity and types of chronic diseases on self-rated memory in older adults in the United States. Data were drawn from the 2011 wave of the National Health and Aging Trends Study (NHATS, N = 6,481). Logistic regressions were used to examine the associations between multimorbidity and types of chronic diseases and fair/poor self-rated memory. Compared to respondents with no or one chronic disease, respondents with multimorbidity showed 35% higher odds of reporting fair/poor self-rated memory. Also, stroke, osteoporosis, and arthritis were identified as increasing the odds of reporting fair/poor self-rated memory by 41%, 20%, and 30%, respectively. Demonstrating the importance of both multimorbidity and types of chronic diseases in self-reporting of memory, our findings suggest the need to educate older adults with multimorbidity and certain types of diseases regarding negative self-rated memory and its consequences.


CotA of Bacillus subtilis is a copper-dependent laccase.
The spore coat protein CotA of Bacillus subtilis displays similarities with multicopper oxidases, including manganese oxidases and laccases. B. subtilis is able to oxidize manganese, but neither CotA nor other sporulation proteins are involved. We demonstrate that CotA is a laccase. Syringaldazine, a specific substrate of laccases, reacted with wild-type spores but not with DeltacotA spores. CotA may participate in the biosynthesis of the brown spore pigment, which appears to be a melanin-like product and to protect against UV light.


Age-related clonal hematopoiesis associated with adverse outcomes.
The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).


Albuminuria, Reduced Kidney Function, and the Risk of ST - and non-ST-segment-elevation myocardial infarction.
Background Chronic kidney disease is a recognized independent risk factor for cardiovascular disease, but whether the risks of ST-segment-elevation myocardial infarction ( STEMI ) and non-ST-segment-elevation myocardial infarction ( NSTEMI ) differ in the chronic kidney disease population is unknown. Methods and Results Using administrative data from Ontario, Canada, we examined patients ≥66 years of age with an outpatient estimated glomerular filtration rate ( eGFR ) and albuminuria measure for incident myocardial infarction from 2002 to 2015. Adjusted Fine and Gray subdistribution hazard models accounting for the competing risk of death were used. In 248 438 patients with 1.2 million person-years of follow-up, STEMI , NSTEMI , and death occurred in 1436 (0.58%), 4431 (1.78%), and 30 015 (12.08%) patients, respectively. The highest level of albumin-to-creatinine ratio (>30 mg/mmol) was associated with a 2-fold higher adjusted risk of both STEMI and NSTEMI among patients with eGFR ≥60 mL/(min·1.73 m2) compared to albumin-to-creatinine ratio <3 mg/mmol. The lowest level of eGFR (<30 mL/[min·1.73 m2]) was not associated with higher STEMI risk but with a 4-fold higher risk of NSTEMI compared to those with eGFR ≥60 mL/(min·1.73 m2). The lowest eGFR (<30 mL/[min·1.73 m2]) and highest albumin-to-creatinine ratio (>30 mg/mmol) were associated with a greater than 4-fold higher risk of both STEMI and NSTEMI (subdistribution hazard models [95% confidence interval] 4.53 [3.30-6.21] and 4.42 [3.67-5.32], respectively) compared to albumin-to-creatinine ratio <3 mg/mmol and eGFR ≥60 mL/(min·1.73 m2). Conclusions Elevations in albuminuria are associated with a higher risk of both NSTEMI and STEMI , regardless of kidney function, whereas reduced kidney function alone is associated with a higher NSTEMI risk.


Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts myofiber organization in the developing limb.
The identities of extracellular growth factors that regulate skeletal muscle development in vivo are largely unknown. We asked if FGFs, which act as repressors of myogenesis in culture, play a similar role in vivo by ectopically expressing in the developing limb a truncated FGF receptor 1 (dnFGFR1) that acts as a dominant negative mutant. Hind limbs and the adjacent somites of Hamburger and Hamilton (HH) stage 17 chickens were infected with a replication-competent RCAS virus encoding dnFGFR1. By ED5, the virus had spread extensively within the limb and the adjacent somites with little rostral or caudal expansion of the infection along the axial midline. Viral infection and mutant receptor expression were coincident as revealed by the distribution of a viral coat protein and an HA epitope tag present on the carboxy terminus of dnFGFR1. Within 48 h following injection of dnFGFR1, we could detect no obvious changes in skeletal muscle precursor cell migration into the hind limb as compared to control limbs infected with an empty RCAN virus. However, by 3 days following infection of RCAS-dnFGFR1 virus, the level of skeletal muscle-specific myosin heavy chain was decreased and the expression pattern altered, suggesting disruption of skeletal muscle development. Two striking muscular phenotypes were observed in dnFGFR1-expressing limbs, including an average loss of 30% in skeletal muscle wet weight and a 50% decrease in myofiber density. At all ages examined the loss of skeletal muscle mass was accompanied by a loss of myoblasts and an unexpected concomitant loss of fibroblasts. Consistent with these observations, explants of infected cells revealed a reduction in the number of myonuclei in myotubes. Although the myofiber density per unit area was decreased over 50% compared to controls there were no detectable effects on myofiber diameter. The loss in myofiber density was, however, accompanied by an increase in the space surrounding individual myofibers and a generalized loss of myofiber integrity. It is noteworthy that long-bone development was unaffected by RCAS-dnFGFR1 infection, suggesting that FGFR2 and FGFR3 signaling was not disrupted. Our data provide conclusive evidence that FGFR1 signaling is necessary to maintain myoblast number and plays a role in myofiber organization.


Surgical resection of pulmonary metastases from colorectal adenocarcinoma. Special reference to repeated pulmonary resections.
Pulmonary resection of metastatic lesions from colorectal adenocarcinoma was performed in 35 patients. The cumulative 5-year survival was 38%. The primary site of cancer was the colon in about half of the patients. Patients with a solitary metastasis or tumors smaller than 3 cm in diameter survived longer than did patients with multiple metastases or tumors larger than 3 cm but the differences were not significant. Other factors, including age, sex, histologic grade of tumor, location and stage of primary carcinoma, location of pulmonary metastases, disease-free interval, and type of pulmonary resection, had no apparent influence on survival time. The lung was the major site of recurrence following pulmonary resection. Seven patients underwent two or more pulmonary resections for metastasis from a colorectal carcinoma. At the time of last follow-up, four patients were alive and free of recurrent disease at 5, 34, 39, and 58 months after the second pulmonary resection. These data suggest that some patients will survive for a long time following pulmonary resection of colorectal metastases, and for highly selected patients, repeated pulmonary resection may further extend survival.


Predictors of improvement in a cognitive-behavioral intervention for women with rheumatoid arthritis.
In this article we present a secondary analysis of data from a brief cognitive-behavioral intervention for women with rheumatoid arthritis that resulted in significant overall improvements in personal coping resources, pain coping behaviors, psychological well-being, and fatigue. Not every participant, however, improved during the intervention. Establishing predictors of improvement in brief interventions is important to optimize the cost-effective use of these resources. In search of predictors of improvement, we examined demographic and background variables, personal coping resources, pain coping behaviors, and social support. Both linear and quadratic effects were analyzed, comparing baseline measures to both immediate postintervention and 3-month follow-up outcomes using standardized indexes ofpredictors and criteria variables. After removing the effects of baseline scores on the outcomes index, significant predictors of improvement included length of time since diagnosis, personal coping resources, and maladaptive and adaptive pain coping behaviors. Both linear and quadratic effects were found, although this varied as a function of type of predictor.


European Network of Bipolar Research Expert Centre (ENBREC): a network to foster research and promote innovative care.
Bipolar disorders rank as one of the most disabling illnesses in working age adults worldwide. Despite this, the quality of care offered to patients with this disorder is suboptimal, largely due to limitations in our understanding of the pathology. Improving this scenario requires the development of a critical mass of expertise and multicentre collaborative projects. Within the framework of the European FP7 programme, we developed a European Network of Bipolar Research Expert Centres (ENBREC) designed specifically to facilitate EU-wide studies. ENBREC provides an integrated support structure facilitating research on disease mechanisms and clinical outcomes across six European countries (France, Germany, Italy, Norway, Spain and the UK). The centres are adopting a standardised clinical assessment that explores multiple aspects of bipolar disorder through a structured evaluation designed to inform clinical decision-making as well as being applicable to research. Reliable, established measures have been prioritised, and instruments have been translated and validated when necessary. An electronic healthcare record and monitoring system (e-ENBREC©) has been developed to collate the data. Protocols to conduct multicentre clinical observational studies and joint studies on cognitive function, biomarkers, genetics, and neuroimaging are in progress; a pilot study has been completed on strategies for routine implementation of psycho-education. The network demonstrates 'proof of principle' that expert centres across Europe can collaborate on a wide range of basic science and clinical programmes using shared protocols. This paper is to describe the network and how it aims to improve the quality and effectiveness of research in a neglected priority area.


Effects of Reducing Antimicrobial Use and Applying a Cleaning and Disinfection Program in Veal Calf Farming: Experiences from an Intervention Study to Control Livestock-Associated MRSA.
With the ultimate aim of containing the emergence of resistant bacteria, a Dutch policy was set in place in 2010 promoting a reduction of antimicrobial use (AMU) in food-producing animals. In this context, a study evaluated strategies to curb livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA). Fifty-one veal calf farms were assigned to one of 3 study arms: RAB farms reducing antimicrobials by protocol; RAB-CD farms reducing antimicrobials by protocol and applying a cleaning and disinfection program; and Control farms without interventions. MRSA carriage was tested in week 0 and week 12 of 2 consecutive production cycles in farmers, family members and veal calves. Interventions were validated and a cyclic rise in MRSA-prevalence in animals was shown with a more moderate increase in RAB farms. Prevalence in humans declined parallel over time in the study arms but RAB farms were at the lowest MRSA levels from the beginning of the study. In RAB-CD farms, human and animal prevalence did not differ from Control farms and MRSA air loads were significantly higher than in the other study arms. Mimicking the national trend, an overall AMU decrease (daily dosages per animal per cycle (DDDA/C)) was observed over 4 pre-study and the 2 study cycles; this trend did not have a significant effect on a set of evaluated farm technical parameters. AMU was positively associated with MRSA across study arms (ORs per 10 DDDA/C increase = 1.26 for both humans (p = 0.07) and animals (p = 0.12 in first cycle)). These results suggest that AMU reduction might be a good strategy for curbing MRSA in veal calf farming, however the specific cleaning and disinfecting program in RAB-CD farms was not effective. The drop in MRSA prevalence in people during the study could be attributed to the observed long-term AMU decreasing trend.


Chronic liver disease: systemic and splanchnic venous flow mapping with optimized cine phase-contrast MR imaging validated in a phantom model and prospectively evaluated in patients.
To validate magnetic resonance (MR) imaging cine phase-contrast blood flow mapping in vitro and in patients with chronic liver disease, with or without portal hypertension, and to assess the accuracy of azygos, splanchnic, and systemic blood flow measured with MR imaging in the detection of high-risk esophageal varices and compare these measurements with endoscopic evaluation, the reference standard. The local ethics committee approved this study. Patients gave written informed consent. Two phantoms were used to validate the MR imaging phase-contrast flow sequence. Patients with liver cirrhosis (n = 59), chronic liver disease without cirrhosis (n = 12), and nodular regenerative hyperplasia (NRH) (n = 11), and healthy control subjects with no liver disease (n = 25) were included. The patients underwent upper digestive system endoscopy. Mean abdominal aorta, portal venous, and azygos blood flow was measured on MR images, which were reviewed by two blinded observers to determine the presence and grade of esophageal varices. The reproducibility and intra- and interobserver variability of the blood flow measurements were assessed with intraclass correlation coefficients (ICCs). The performance of the MR blood flow measurements in staging high-risk varices was determined with receiver operating characteristic curve analysis. The correlation between MR visual analysis and endoscopic grading was assessed by using κ statistics. MR flow rate measurements had excellent correlations with actual flow values in vitro (ICC > 0.990 for phantoms 1 and 2). Mean aortic flow was significantly higher in patients with cirrhosis than in control subjects (P < .001). Mean azygos flow was significantly higher in patients with cirrhosis than in patients with chronic liver disease without cirrhosis (P = .005) and control subjects (P < .001). Low intra- and interobserver variability (ICC > 0.990 for each blood flow type) and high reproducibility (ICC > 0.850 for each blood flow type) were demonstrated. The optimal cutoff mean azygos flow value was 2.3 mL/sec for varices with grades of 2 or higher. MR imaging azygos flow measurement appears to be a promising technique for detecting high-risk esophageal varices in patients with portal hypertension.


Non-psychotic mental disorders in the perinatal period.
Mental disorders are among the most common morbidities of pregnancy and the postnatal period, and can have adverse effects on the mother, her child, and family. This Series paper summarises the evidence about epidemiology, risk factors, identification, and interventions for non-psychotic mental disorders. Although the phenomenology and risk factors for perinatal mental disorders are largely similar to those for the disorders at other times, treatment considerations differ during pregnancy and breastfeeding. Most randomised controlled trials have examined psychosocial and psychological interventions for postnatal depression, with evidence for effectiveness in treating and preventing the disorder. Few high-quality studies exist on the effectiveness or safety of pharmacological treatments in the perinatal period, despite quite high prescription rates. General principles of prescribing of drugs in the perinatal period are provided, but individual risk-benefit analyses are needed for decisions about treatment.


Incorporating simulation technology into a neurology clerkship.
Simulation-based medical education is growing in use and popularity in various settings and specialties. A literature review yields scant information about the use of simulation-based medical education in neurology, however. The specialty of neurology presents an interesting challenge to the field of simulation-based medical education because of the inability of even the most advanced mannequins to mimic a focal neurologic deficit. The authors present simulator protocols for status epilepticus and acute stroke that use a high-fidelity mannequin despite its inability to mimic a focal neurologic deficit. These protocols are used in the training of third- and fourth-year medical students during their neurology clerkship at Penn State College of Medicine. The authors also provide a review of the pertinent literature.


Mouse models of membranous nephropathy: the road less travelled by.
Membranous nephropathy (MN) is a major cause of idiopathic nephrotic syndrome in adults, often progressing to end-stage kidney disease. The disease is mediated by IgG antibodies that form subepithelial immune complexes upon binding to antigens expressed by podocytes or planted in the subepithelial space. Subsequent activation of the complement cascade, podocyte injury by the membrane attack complex and the expansion of the glomerular basement membrane cause proteinuria and nephrotic syndrome. The blueprint for our current understanding of the pathogenic mechanisms of MN has largely been provided by studies in rat Heymann nephritis, an excellent animal model that closely replicates human disease. However, further progress in this area has been hindered by the lack of robust mouse models of MN that can leverage the power of genetic approaches for mechanistic studies. This critical barrier has recently been overcome by the development of new mouse models that faithfully recapitulate the clinical and morphologic hallmarks of human MN. In these mouse models, subepithelial ICs mediating proteinuria and nephrotic syndrome are induced by injection of cationized bovine serum albumin, by passive transfer of heterologous anti-podocyte antibodies, or by active immunization with the NC1 domain of α3(IV) collagen. These mouse models of MN will be instrumental for addressing unsolved questions about the basic pathomechanisms of MN and also for preclinical studies of novel therapeutics. We anticipate that the new knowledge to be gained from these studies will eventually translate into much needed novel mechanism-based therapies for MN, more effective, more specific, and less toxic.


Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies.
Brimonidine tartrate, a highly selective α2-adrenergic receptor agonist with potent vasoconstrictive activity, was shown to reduce erythema of rosacea. To assess the efficacy and safety of topical brimonidine tartrate gel 0.5% for the treatment of erythema of rosacea. Both studies were randomized, double-blind, and vehicle-controlled, with identical design. Subjects with moderate to severe erythema of rosacea were randomized 1:1 to apply topical brimonidine tartrate gel 0.5% or vehicle gel once-daily for 4 weeks, followed by a 4-week follow-up phase. Evaluations included severity of erythema based on Clinician's Erythema Assessment and Patient's Self-Assessment, as well as adverse events. Topical brimonidine tartrate gel 0.5% was significantly more efficacious than vehicle gel throughout 12 hours on days 1, 15, and 29, with significant difference observed as early as 30 minutes after the first application on day 1 (all P<.001). No tachyphylaxis, rebound or aggravation of other disease signs were observed. Slightly higher incidence of adverse events was observed for topical brimonidine tartrate gel 0.5% than for vehicle; however, most of the adverse events were dermatological, mild, and transient in nature. These data generated in controlled trials may be different from those in clinical practice. Once-daily brimonidine tartrate gel 0.5% has a good safety profile and provides significantly greater efficacy relative to vehicle gel for the treatment of moderate to severe erythema of rosacea, as early as 30 minutes after application.


Relatedness disequilibrium regression estimates heritability without environmental bias.
Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.