Development of an integrated electronic platform for patient self-report and management of adverse events during cancer treatment.
Significant adverse events (AE) during cancer therapy disrupt treatment and escalate to emergency admissions. Approaches to improve the timeliness and accuracy of AE reporting may improve safety and reduce health service costs. Reporting AE via patient reported outcomes (PROs), can improve clinician-patient communication and making data available to clinicians in 'real-time' using electronic PROs (ePROs) could potentially transform clinical practice by providing easily accessible records to guide treatment decisions. This manuscript describes the development of eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice) is a National Institute for Health Research-funded programme, a system for patients to self-report and manage AE online during and after cancer treatment. A multidisciplinary team of IT experts, staff and patients developed using agile principles a secure web application interface (QStore) between an existing online questionnaire builder (QTool) displaying real-time ePRO data to clinicians in the electronic patient record at Leeds Teaching Hospitals NHS Trust. Hierarchical algorithms were developed corresponding to Common Terminology Criteria for Adverse Events grading using the QTool question dependency function. Patient advocates (N = 9), patients (N = 13), and staff (N = 19) usability tested the system reporting combinations of AE. The eRAPID system allows patients to report AE from home on PC, tablet or any web enabled device securely during treatment. The system generates immediate self-management advice for low or moderate AE and for severe AE advice to contact the hospital immediately. Clinicians can view patient AE data in the electronic patient record and receive email notifications when patients report severe AE. Evaluation of the system in a randomised controlled trial in breast, gynaecological and colorectal cancer patients undergoing systemic therapy is currently underway. To adapt eRAPID for different treatment groups, pilot studies are being undertaken with patients receiving pelvic radiotherapy and upper gastrointestinal surgery. ISRCTN88520246.


Universal single-probe RT-PCR assay for diagnosis of dengue virus infections.
Dengue is a mosquito-borne viral disease that has become more prevalent in the last few decades. Most patients are viremic when they present with symptoms, and early diagnosis of dengue is important in preventing severe clinical complications associated with this disease and also represents a key factor in differential diagnosis. Here, we designed and validated a hydrolysis-probe-based one-step real-time RT-PCR assay that targets the genomes of dengue virus serotypes 1-4. The primers and probe used in our RT-PCR assay were designed to target the 3' untranslated region of all complete genome sequences of dengue virus available in GenBank (n = 3,305). Performance of the assay was evaluated using in vitro transcribed RNA, laboratory-adapted virus strains, external control panels, and clinical specimens. The linear dynamic range was found to be 104-1011 GCE/mL, and the detection limit was between 6.0×102 and 1.1×103 GCE/mL depending on target sequence. The assay did not cross-react with human RNA, nor did it produce false-positive results for other human pathogenic flaviviruses or clinically important etiological agents of febrile illnesses. We used clinical serum samples obtained from returning travelers with dengue-compatible symptomatology (n = 163) to evaluate the diagnostic relevance of our assay, and laboratory diagnosis performed by the RT-PCR assay had 100% positive agreement with diagnosis performed by NS1 antigen detection. In a retrospective evaluation including 60 archived serum samples collected from confirmed dengue cases 1-9 days after disease onset, the RT-PCR assay detected viral RNA up to 9 days after appearance of symptoms. The validation of the RT-PCR assay presented here indicates that this technique can be a reliable diagnostic tool, and hence we suggest that it be introduced as the method of choice during the first 5 days of dengue symptoms.


Time course of the subjective emotional response to aversive pictures: relevance to fMRI studies.
Using functional magnetic resonance imaging (fMRI) to study brain activity related to the experience of emotion presents unique challenges to neuroscientists. One important consideration arises when an experimentally induced subjective emotional response persists after the end of the emotional stimulation epoch. In this case, brain activity related to the emotional response may continue during the subsequent control or comparison epoch. The comparison epoch of the experiment may then contain a lingering emotional response. This study was conducted to better understand the time course of the subjective emotional response to intensely aversive pictures, with the goal of applying this knowledge to the design and analysis of fMRI studies of emotion. A total of 18 women in two separate experiments were shown a series of aversive, neutral and scrambled pictures presented in alternating block designs. Subjects rated the intensity of their negative feelings every 4 s while viewing the pictures. Results indicate that the subjective emotional response persists well after the end of the emotional stimulation epoch. Following a 16-s block of aversive pictures, an average of an additional 16 s elapsed before self-reported negative feelings showed a 74-80% decline. These data suggest that fMRI studies of emotion should consider the time course of the subjective response to emotionally laden stimuli.


Neurocranial development of the coelacanth and the evolution of the sarcopterygian head.
The neurocranium of sarcopterygian fishes was originally divided into an anterior (ethmosphenoid) and posterior (otoccipital) portion by an intracranial joint, and underwent major changes in its overall geometry before fusing into a single unit in lungfishes and early tetrapods1. Although the pattern of these changes is well-documented, the developmental mechanisms that underpin variation in the form of the neurocranium and its associated soft tissues during the evolution of sarcopterygian fishes remain poorly understood. The coelacanth Latimeria is the only known living vertebrate that retains an intracranial joint2,3. Despite its importance for understanding neurocranial evolution, the development of the neurocranium of this ovoviviparous fish remains unknown. Here we investigate the ontogeny of the neurocranium and brain in Latimeria chalumnae using conventional and synchrotron X-ray micro-computed tomography as well as magnetic resonance imaging, performed on an extensive growth series for this species. We describe the neurocranium at the earliest developmental stage known for Latimeria, as well as the major changes that the neurocranium undergoes during ontogeny. Changes in the neurocranium are associated with an extreme reduction in the relative size of the brain along with an enlargement of the notochord. The development of the notochord appears to have a major effect on the surrounding cranial components, and might underpin the formation of the intracranial joint. Our results shed light on the interplay between the neurocranium and its adjacent soft tissues during development in Latimeria, and provide insights into the developmental mechanisms that are likely to have underpinned the evolution of neurocranial diversity in sarcopterygian fishes.


One health: the importance of companion animal vector-borne diseases.
The international prominence accorded the 'One Health' concept of co-ordinated activity of those involved in human and animal health is a modern incarnation of a long tradition of comparative medicine, with roots in the ancient civilizations and a golden era during the 19th century explosion of knowledge in the field of infectious disease research. Modern One Health tends to focus on zoonotic pathogens emerging from wildlife and production animal species, but one of the most significant One Health challenges is rabies for which there is a canine reservoir. This review considers the role of small companion animals in One Health and specifically addresses the major vector-borne infectious diseases that are shared by man, dogs and cats. The most significant of these are leishmaniosis, borreliosis, bartonellosis, ehrlichiosis, rickettsiosis and anaplasmosis. The challenges that lie ahead in this field of One Health are discussed, together with the role of the newly formed World Small Animal Veterinary Association One Health Committee.


Experience, training and confidence among small, non-community drinking water system operators in Ontario, Canada.
The water operator plays an important role in water safety; however, little published research exists that has examined this role. The purpose of this study was to develop a greater understanding of the experience, existing knowledge, confidence and future training needs of the small, non-community drinking water operator in Ontario in order to help guide future outreach and training opportunities. A cross-sectional telephone survey of 332 small, non-community drinking water operators in Ontario was conducted in July and August 2011. Survey questions pertained to respondents' experience as operators, formal training, perceived importance of water safety issues, confidence in handling water safety issues, and future training needs. Approximately 16% (54/330) of respondents had one year or less experience as a water operator, and 60% (199/332) reported that being a water operator was not a chosen profession. Only 37% (124/332) of operators reported completing operator training. Respondents reported a preference for online training courses or on-site training (compared with a classroom setting). Low training rates, inexperience, and in certain situations, low confidence, among many small water system operators highlight a need to provide continued support to the development of ongoing training opportunities in this population.


MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.
MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.


Reliability of sickness certificates in detecting potential sick leave reduction by modifying working conditions: a clinical epidemiology study.
Medical sickness certificates are generally the main source for information when scrutinizing the need for aimed intervention strategies to avoid or reduce the individual and community side effects of sick leave. This study explored the value of medical sickness certificates related to daily work in Norwegian National Insurance Offices to identify sick-listed persons, where modified working conditions might reduce the ongoing sick leave. The potential for reducing the ongoing sick leave by modifying working conditions was individually assessed on routine sickness certificates in 999 consecutive sick leave episodes by four Norwegian National Insurance collaborators, two with and two without formal medical competence. The study took place in Northern Norway in 1997 and 1998. Agreement analysed with differences against mean, kappa, and proportional-agreement analysis within and between groups of assessors was used in the judgement. Agreements between the assessors and the self-assessment of sick-listed subjects were additionally analysed in 159 sick-leave episodes. Both sick-listed subjects and National Insurance collaborators anticipated a potential reduction in sick leave in 20-30% of cases, and in another 20% the potential was assessed as possible. The chance corrected agreements, however, were poor (k < 0.20) within and between groups of National Insurance collaborators. The agreement between National Insurance collaborators and the sick-listed subjects was no better than chance. Neither extended medical information nor formal medical competence increased agreement in cases where modified working conditions might have reduced sick leave. Information in medical sickness certificates proved ineffective in detecting cases where modified working conditions may reduce sick leave, and focusing on medical certificates may prevent identification of needed interventions. Strategies on how to communicate directly with sick-listed subjects would enable social authorities to exploit more of the sick leave reduction potential by modifying the working conditions than strategies on improving medical information.


Kinetics of release of serotonin from isolated secretory granules. II. Ion exchange determines the diffusivity of serotonin.
We measured the efflux of 5-hydroxytryptamine (5-HT, serotonin) from an intact secretory granule extracted from the mast cell of the beige mouse. The efflux was measured with amperometry after rupture of the granule membrane was triggered by electroporation. We determined the diffusivity of 5-HT within the secretory granule to be 2.0 x 10(-8) cm2 s(-1) when the granule is in contact with a physiological saline and found that this diffusivity depends on the valence of the cation in the external electrolyte. There is a fivefold increase in the diffusion coefficient of 5-HT determined in CsCl (150 mM, pH 7.2) at 3.7 x 10(-8) cm2 s(-1) compared to that determined in histamine dihydrochloride (Hi, 100 mM at pH 4.5) at 0.7 x 10(-8) cm2 s(-1). We found that the rate of expansion of the granule matrix observed in physiological medium correlates with the efflux of 5-HT, and that the rate of swelling of the matrix and the efflux depend on the microviscosity within the granule matrix and not the bulk viscosity of the external solution. The low diffusivity of 5-HT (approximately 500-fold less than in the bulk), the observation that the valence of the counterion affects this diffusivity, and the relationship between the volume changes of the matrix and the efflux suggest that 5-HT is released from the granule by ion exchange. We discuss the implications of this result for exocytotic release in mast cells and propose that an ion exchange mechanism could control the rate of release in other secretory systems.


No effect of low-dose aspirin for the prevention of heterotopic bone formation after total hip replacement: a randomized trial of 2,649 patients.
2,649 patients scheduled for elective total hip replacement were recruited to the Heterotopic Bone Formation Sub-study of the Pulmonary Embolism Prevention Trial. Heterotopic bone formation was determined by radiographic examination and associated late postoperative outcomes were assessed by telephone interview. Heterotopic bone formation was observed in 627 (31%) of 2,048 radiographic examinations. There was no detectable effect of low-dose aspirin on the risks of heterotopic bone formation (RR 0.98; 95% CI 0.85-1.12), late postoperative pain (RR 1.10; 95%CI 0.91-1.35) or late postoperative impaired function (RR 1.03; 95% CI 0.94-1.12). The balance of benefits and risks of low-dose aspirin is determined by its effects on vascular events and bleeding, since it has no major effects on heterotopic bone formation or associated clinical outcomes.


Transcriptome analysis of Aspergillus nidulans exposed to camptothecin-induced DNA damage.
We have used an Aspergillus nidulans macroarray carrying sequences of 2,787 genes from this fungus to monitor gene expression of both wild-type and uvsB(ATR) (the homologue of the ATR gene) deletion mutant strains in a time course exposure to camptothecin (CPT). The results revealed a total of 1,512 and 1,700 genes in the wild-type and uvsB(ATR) deletion mutant strains that displayed a statistically significant difference at at least one experimental time point. We characterized six genes that have increased mRNA expression in the presence of CPT in the wild-type strain relative to the uvsB(ATR) mutant strain: fhdA (encoding a forkhead-associated domain protein), tprA (encoding a hypothetical protein that contains a tetratrico peptide repeat), mshA (encoding a MutS homologue involved in mismatch repair), phbA (encoding a prohibitin homologue), uvsC(RAD51) (the homologue of the RAD51 gene), and cshA (encoding a homologue of the excision repair protein ERCC-6 [Cockayne's syndrome protein]). The induced transcript levels of these genes in the presence of CPT require uvsB(ATR). These genes were deleted, and surprisingly, only the DeltauvsC mutant strain was sensitive to CPT; however, the others displayed sensitivity to a range of DNA-damaging and oxidative stress agents. These results indicate that the selected genes when inactivated display very complex and heterogeneous sensitivity behavior during growth in the presence of agents that directly or indirectly cause DNA damage. Moreover, with the exception of UvsC, deletion of each of these genes partially suppressed the sensitivity of the DeltauvsB strain to menadione and paraquat. Our results provide the first insight into the overall complexity of the response to DNA damage in filamentous fungi and suggest that multiple pathways may act in parallel to mediate DNA repair.


Comparative Risk Analysis of Two Culicoides-Borne Diseases in Horses: Equine Encephalosis More Likely to Enter France than African Horse Sickness.
African horse sickness (AHS) and equine encephalosis (EE) are Culicoides-borne viral diseases that could have the potential to spread across Europe if introduced, thus being potential threats for the European equine industry. Both share similar epidemiology, transmission patterns and geographical distribution. Using stochastic spatiotemporal models of virus entry, we assessed and compared the probabilities of both viruses entering France via two pathways: importation of live-infected animals or importation of infected vectors. Analyses were performed for three consecutive years (2010-2012). Seasonal and regional differences in virus entry probabilities were the same for both diseases. However, the probability of EE entry was much higher than the probability of AHS entry. Interestingly, the most likely entry route differed between AHS and EE: AHS has a higher probability to enter through an infected vector and EE has a higher probability to enter through an infectious host. Consequently, different effective protective measures were identified by 'what-if' scenarios for the two diseases. The implementation of vector protection on all animals (equine and bovine) coming from low-risk regions before their importation was the most effective in reducing the probability of AHS entry. On the other hand, the most significant reduction in the probability of EE entry was obtained by the implementation of quarantine before import for horses coming from both EU and non-EU countries. The developed models can be useful to implement risk-based surveillance.


Non-Surgical Interventions for Lumbar Spinal Stenosis Leading To Neurogenic Claudication: A Clinical Practice Guideline.
Lumbar spinal stenosis (LSS) causing neurogenic claudication (NC) is increasingly common with an aging population and can be associated with significant symptoms and functional limitations. We developed this guideline to present the evidence and provide clinical recommendations on nonsurgical management of patients with LSS causing NC. Using the GRADE approach, a multidisciplinary guidelines panel based recommendations on evidence from a systematic review of randomized controlled trials and systematic reviews published through June 2019, or expert consensus. The literature monitored up to October 2020. Clinical outcomes evaluated included pain, disability, quality of life, and walking capacity. The target audience for this guideline includes all clinicians, and the target patient population includes adults with LSS (congenital and/or acquired, lateral recess or central canal, with or without low back pain, with or without spondylolisthesis) causing NC. The guidelines panel developed 6 recommendations based on randomized controlled trials and 5 others based on professional consensus, summarized in 3 overarching recommendations: (Grade: statements are all conditional/weak recommendations) Recommendation 1. For patients with LSS causing NC, clinicians and patients may initially select multimodal care nonpharmacological therapies with education, advice and lifestyle changes, behavioral change techniques in conjunction with home exercise, manual therapy, and/or rehabilitation (moderate-quality evidence), traditional acupuncture on a trial basis (very low-quality evidence), and postoperative rehabilitation (supervised program of exercises and/or educational materials encouraging activity) with cognitive-behavioral therapy 12 weeks postsurgery (low-quality evidence). Recommendation 2. In patients LSS causing NC, clinicians and patients may consider a trial of serotonin-norepinephrine reuptake inhibitors or tricyclic antidepressants. (very low-quality evidence). Recommendation 3. For patients LSS causing NC, we recommend against the use of the following pharmacological therapies: nonsteroidal anti-inflammatory drugs, methylcobalamin, calcitonin, paracetamol, opioids, muscle relaxants, pregabalin (consensus-based), gabapentin (very low-quality), and epidural steroidal injections (high-quality evidence). PERSPECTIVE: This guideline, on the basis of a systematic review of the evidence on the nonsurgical management of lumbar spine stenosis, provides recommendations developed by a multidisciplinary expert panel. Safe and effective non-surgical management of lumbar spine stenosis should be on the basis of a plan of care tailored to the individual and the type of treatment involved, and multimodal care is recommended in most situations.


[Hearing health of workers exposed to noise and insecticides].
To examine the peripheral auditory disorders in a group of workers exposed to organophosphate and pyrethroid insecticides, used in vector control campaigns. The prevalence study examined a population of 98 individuals who sprayed insecticides in campaigns for the prevention of Dengue, Chagas disease and Yellow fever. The sampling approach was finalistic, and included the workers in a health district of Pernambuco, during the year 2000. A questionnaire was used to collect data on occupational and non-occupational risks, safety measures utilized, family history of auditory problems and health symptoms. Previous noise exposure history was also investigated, since noise can be a confounding factor for hearing loss. Hearing sensitivity and middle ear function were assessed by pure tone audiometry. Among those exposed to insecticides, 63.8% demonstrated a hearing loss. For the group of workers exposed to both noise and insecticides, hearing loss was observed in 66.7% of the cases. The median exposure time necessary to detect high-frequency losses was 3.4 years for workers exposed to both agents and 7.3 years for workers exposed to insecticides only. Hearing thresholds were poorest among workers exposed to both agents. Auditory damage for those with combined exposures to the two factors was more severe than the hearing losses observed among those exposed only to insecticides. There is evidence that exposure to insecticides was associated with peripheral sensorioneural hearing loss and that noise exposure can potentiate the ototoxic effects of insecticides. It is necessary to evaluate this possible association through epidemiological studies.


Increased risk of early vomiting among infants and young children treated with dihydroartemisinin-piperaquine compared with artemether-lumefantrine for uncomplicated malaria.
Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are highly efficacious antimalarial therapies in Africa. However, there are limited data regarding the tolerability of these drugs in young children. We used data from a randomized control trial in rural Uganda to compare the risk of early vomiting (within one hour of dosing) for children 6-24 months of age randomized to receive DP (n = 240) or AL (n = 228) for treatment of uncomplicated malaria. Overall, DP was associated with a higher risk of early vomiting than AL (15.1% versus 7.1%; P = 0.007). The increased risk of early vomiting with DP was only present among breastfeeding children (relative risk [RR] = 3.35, P = 0.001) compared with children who were not breastfeeding (RR = 1.03, P = 0.94). Age less than 18 months was a risk factor for early vomiting independent of treatment (RR = 3.27, P = 0.02). Our findings indicate that AL may be better tolerated than DP among young breastfeeding children treated for uncomplicated malaria.


How Much Time Do Families Spend on the Health Care of Children with Diabetes?
Family time caring for children with diabetes is an overlooked component of the overall burden of the condition. We document and analyze risk factors for time family members spend providing health care at home and arranging/coordinating health care for children with diabetes. Data for 755 diabetic children and 16,161 non-diabetic children whose chronic conditions required only prescription (Rx) medication were from the 2009-2010 United States National Survey of Children with Special Health Care Needs (NS-CSHCN). We used generalized ordered logistic regressions to estimate adjusted odds ratios (AORs) of time burden by diabetes, insulin use, and stability of the child's health care needs, controlling for health and socioeconomic status. Nearly one-quarter of diabetic children had family members who spent 11+ h/week providing health care at home, and 8% spent 11+ h/week arranging/coordinating care, compared with 3.3% and 1.9%, respectively, of non-diabetic Rx-only children. Time providing care at home for insulin-using children was concentrated in the higher time categories: AORs for insulin-using diabetic compared to non-diabetic Rx-only children were 4.4 for 1+ h/week compared with <1 h/week, 9.7 for 6+ vs. <6 h, and 12.4 for 11+ vs. <11 h (all P < 0.05); the pattern was less pronounced for non-insulin-using children. AORs for arranging/coordinating care did not vary by time contrast: AOR = 4.2 for insulin-using, 3.0 for non-insulin-using children. Health care providers, school personnel, and policymakers need to work with family members to improve care coordination and identify other ways to reduce family time burdens caring for children with diabetes.


The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study.
Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease-modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established. To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA. All patients on anti-TNF agents and conventional DMARDs within the Swiss Clinical Quality Management (SCQM)-RA database were included (n = 1218) and categorised according to the type of co-therapy into anti-TNF+MTX (n = 842), anti-TNF+LEF (n = 260) and anti-TNF+other DMARDs (n = 116). Drug discontinuation rates and incidence of toxic side effects were analysed using Cox proportional hazard models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analysed using longitudinal regression models, adjusting for potential confounders. The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (interquartile range (IQR): 10-37), but they did not differ between the three regimens (p = 0.69). The progression of radiographic damage (p = 0.77), functional disability (p = 0.09) and RA disease activity (p = 0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.


Influence of aromatase absence on the gene expression and histology of the mouse meibomian gland.
We hypothesize that aromatase, an enzyme that controls estrogen biosynthesis, plays a major role in the sex-related differences of the meibomian gland. To begin to test this hypothesis, we examined the influence of aromatase absence, which completely eliminates estrogen production, on glandular gene expression and histology in male and female mice. Meibomian glands were obtained from adult, age-matched wild-type (WT) and aromatase knockout (ArKO) mice. Tissues were processed for histology or the isolation of total RNA, which was analyzed for differentially expressed mRNAs by using microarrays. Our results show that aromatase significantly influences the expression of more than a thousand genes in the meibomian gland. The nature of this effect is primarily sex-dependent. In addition, the influence of aromatase on sex-related differences in gene expression is predominantly genotype-specific. However, many of the sex-related variations in biological process, molecular function, and cellular component ontologies, as well as in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, are remarkably similar between WT and ArKO mice. The loss of aromatase activity has no obvious effect on the histology of meibomian glands in male or female mice. Our findings demonstrate that aromatase has a significant impact on gene expression in the meibomian gland. The nature of this influence is sex-dependent and genotype-specific; however, many of the sex-related variations in gene ontologies and KEGG pathways are similar between WT and ArKO mice. Consequently, it appears that aromatase, and by extension estrogen, do not play a major role in the sex-related differences of the mouse meibomian gland.


Interprofessional education in academic family medicine teaching units: a functional program and culture.
The new family health teams (FHTs) in Ontario were designed to enable interprofessional collaborative practice in primary care; however, many health professionals have not been trained in an interprofessional environment. To provide health professional learners with an interprofessional practice experience in primary care that models teamwork and collaborative practice skills. The 2 academic teaching units of the FHT at McMaster University in Hamilton, Ont, employ 6 types of health professionals and provide learning environments for family medicine residents and students in a variety of health care professions. Learners engage in formal interprofessional education activities and mixed professional and learner clinical consultations. They are immersed in an established interprofessional practice environment, where all team members are valued and contribute collaboratively to patient care and clinic administration. Other contributors to the success of the program include the physical layout of the clinics, the electronic medical record communications system, and support from leadership for the additional clinical time commitment of delivering interprofessional education. This academic FHT has developed a program of interprofessional education based partly on planned activities and logistic enablers, and largely on immersing learners in a culture of long-standing interprofessional collaboration.


Estradiol measurement in translational studies of breast cancer.
Plasma estrogen measurement with use of radioimmunoassays has been instrumental in the development of aromatase inhibitors for endocrine therapy of postmenopausal breast cancer. However, due to low plasma estrogen concentrations in postmenopausal women, direct radioimmunoassays lack the sensitivity required. While certain laboratories have developed highly sensitive assays for research purposes revealing plasma estrogen suppression consistent with results from tracer studies, such assays are time and labor-consuming due to need for pre-analytical chromatographic purification, sample concentration and sometimes conversion of precursors to products. While novel chromatographic methods involving mass spectrometry analysis are likely to replace such radioimmunoassays in the future, so far a limited number of laboratories have developed suitable assays with a detection limit (around 1 pM) that is required for analyzing plasma estrogen levels in patients during treatment with potent aromatase inhibitors.


Development, characterization and diagnostic application of a monoclonal antibody specific for a proteinase K resistant Lawsonia intracellularis antigen.
Proliferative enteropathy (PE) is one of the most important infections in pigs caused by Lawsonia intracellularis, an obligate intracellular bacterium. The purpose of the present investigation was to develop monoclonal antibodies with specificity to L. intracellularis useful both for diagnostic purposes (by immunohistochemistry) and for bacterial characterization. Several antibody producing hybridomas were established by fusion of mouse myeloma with spleen cells from BALB/c mice immunized with mucosa scrapings of the intestinal mucosa from a L. intracellularis infected pig. A monoclonal antibody (mAb), Law1-DK, isotyped as IgG2b was selected by indirect immunofluorescence antibody test (IFAT). Histological sections of the intestines from pigs affected by proliferative enteropathy and in vitro grown bacteria in cell culture were tested positive for the presence of L. intracellularis with the mAb. A molecule at 21 kDa was recognized by the mAb in a Western blotting analysis when a whole-cell preparation of L. intracellularis was run on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This antigen was released from L. intracellularis by mild heat treatment and was resistant to proteinase K digestion, suggesting it to be non-protein, e.g., lipopolysaccharide (LPS). This suggestion was supported by its presence in the aqueous phase of a phenol-water extract. The inhibitory effect of periodate oxidation on the antigen-antibody binding confirmed the participation of a carbohydrate epitope. The new mAb was tested highly specific for L. intracellularis by applying in situ hybridization with a L. intracellularis specific probe targeting 16S ribosomal RNA simultaneously with the IFAT.


Identifying mismatches in alignments of large anatomical ontologies.
The objective of this study is to propose a model of matching errors for identifying mismatches in alignments of large anatomical ontologies. Meth-ods: Three approaches to identifying mismatches are utilized: 1) lexical, based on the presence of modifiers in the names of the concepts aligned; 2) structural, identifying conflicting relations resulting from the alignment; and 3) semantic, based on disjoint top-level categories across ontologies. 83% of the potential mismatches identified by the HMatch system are identified by at least one of the approaches. Although not a substitute for a careful validation of the matches, these approaches significantly reduce the need for manual validation by effectively characterizing most mismatches.


Cultured human neural cells accumulate a heat-shock protein during acute herpes simplex virus infection.
Herpes simplex virus-1 (HSV-1) infection of cultured human neural cells causes the accumulation of a host cell-encoded nuclear protein identified as a 57,000 mol.wt. stress protein by monoclonal antibody TI56. This protein is cell cycle-related in fibroblast, may mediate host cell control during HSV infection and could play a role in the regulation of HSV latency.


Assessment of the Accuracy of Using ICD-9 Codes to Identify Uveitis, Herpes Zoster Ophthalmicus, Scleritis, and Episcleritis.
With the increased use of data from electronic medical records for research, it is important to validate International Classification of Diseases, Ninth Revision (ICD-9) codes for their respective diagnoses. To assess the accuracy of using ICD-9 codes to identify ocular inflammatory diseases. Retrospective secondary database analysis. The setting was Kaiser Permanente Hawaii, an integrated managed care consortium that serves approximately 15% of the general Hawaiian population. Participants were patients with ICD-9 diagnosis codes that might be associated with a diagnosis of ocular inflammation seen at Kaiser Permanente Hawaii between January 1, 2006, and December 31, 2007. The data collection and analysis took place from January 2011 to August 2015. The main outcome was the positive predictive value (PPV) of ICD-9 codes for identifying specific types of ocular inflammatory disease. The PPVs were calculated by determining the ratio of the confirmed cases found by medical record review to the total number of cases identified by ICD-9 code. Of the 873 patients identified by a comprehensive list of ICD-9 codes for ocular inflammatory diseases, 224 cases were confirmed as uveitis after medical record review. Using a set of uveitis-specific codes and eliminating patients with a history of ocular surgery, the overall PPV for uveitis was 61% (95% CI, 56%-66%). The PPVs for individual uveitis codes ranged from 0% to 100%, and 11 uveitis codes had a PPV exceeding 80%. Herpes zoster ophthalmicus and scleritis/episcleritis ICD-9 codes had PPVs of 91% (95% CI, 86%-95%) and 60% (95% CI, 54%-66%), respectively. Our results suggest that using ICD-9 codes alone to capture uveitis and scleritis/episcleritis diagnoses is not sufficient in the Kaiser Permanente Hawaii healthcare system, although there were specific uveitis codes with high PPVs. However, the electronic medical record can reliably be used to identify herpes zoster ophthalmicus cases. Medical record review, as was done in this study, is recommended to elucidate diagnoses for uveitis and scleritis/episcleritis.


Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.
Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.


Adsorption of hematite nanoparticles onto Caco-2 cells and the cellular impairments: effect of particle size.
The increasing applications of engineered nanomaterials nowadays have elevated the potential of human exposure through various routes including inhalation, skin penetration and digestion. To date there is scarce information on a quantitative description of the interactions between nanoparticles (NPs) and cell surfaces and the detrimental effects from the exposure. The purpose of this work was to study in vitro exposure of Caco-2 cells to hematite (alpha-Fe(2)O(3)) NPs and to determine the particle size effects on the adsorption behaviors. Cellular impairment was also investigated and compared. Hematite NPs were synthesized as part of this study with a discrete size distribution and uniform morphology examined by dynamic light scattering (DLS) and confirmed by transmission electron microscopy (TEM). Caco-2 cells were cultured as a model epithelium to mirror human intestinal cells and used to evaluate the impacts of the exposure to NPs by measuring transepithelial electrical resistance (TEER). Cell surface disruption, localization and translocation of NPs through the cells were analyzed with immunocytochemical staining and confocal microscopy. Results showed that hematite NPs had mean diameters of 26, 53, 76 and 98 nm and were positively charged with minor aggregation in the buffer solution. Adsorption of the four sizes of NPs on cells reached equilibrium within approximately 5 min but adsorption kinetics were found to be size-dependent. The adsorption rates expressed as mg m(-2) min(-1) were greater for large NPs (76 and 98 nm) than those for small NPs (26 and 53 nm). However, adsorption rates, expressed in units of m(-2) min(-1), were much greater for small NPs than large ones. After the adsorption equilibrium was reached, the adsorbed mass of NPs on a unit area of cells was calculated and showed no significant size dependence. Longer exposure time (>3 h) induced adverse cellular effects as indicated by the drop in TEER compared to the control cells without the exposure to NPs. NPs initially triggered a dynamic reorganization and detachment of microvilli structures on Caco-2 cell surfaces. Following this impact, the drop in TEER occurred more significantly, particularly for the exposure to 26 nm NPs, which was consistent with the observations with confocal microscopy that the junctions were more severely disrupted by 26 nm NPs than other sizes. In conclusion, this paper demonstrates the interactions at the ultrastructural level from initial surface adsorption of NPs upon cells, to the subsequent microvilli reorganization, membrane penetration and the disruption of adherens junction and provides the fundamental information on size effects on NP behavior which is often poorly addressed for in vitro cytotoxicity studies of NPs.


Delayed antibiotic prescriptions for respiratory infections.
Concerns exist regarding antibiotic prescribing for respiratory tract infections (RTIs) owing to adverse reactions, cost, and antibacterial resistance. One proposed strategy to reduce antibiotic prescribing is to provide prescriptions, but to advise delay in antibiotic use with the expectation that symptoms will resolve first. This is an update of a Cochrane Review originally published in 2007, and updated in 2010 and 2013. To evaluate the effects on clinical outcomes, antibiotic use, antibiotic resistance, and patient satisfaction of advising a delayed prescription of antibiotics in respiratory tract infections. For this 2017 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 4, 2017), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register; Ovid MEDLINE (2013 to 25 May 2017); Ovid Embase (2013 to 2017 Week 21); EBSCO CINAHL Plus (1984 to 25 May 2017); Web of Science (2013 to 25 May 2017); WHO International Clinical Trials Registry Platform (1 September 2017); and ClinicalTrials.gov (1 September 2017). Randomised controlled trials involving participants of all ages defined as having an RTI, where delayed antibiotics were compared to immediate antibiotics or no antibiotics. We defined a delayed antibiotic as advice to delay the filling of an antibiotic prescription by at least 48 hours. We considered all RTIs regardless of whether antibiotics were recommended or not. We used standard Cochrane methodological procedures. Three review authors independently extracted and collated data. We assessed the risk of bias of all included trials. We contacted trial authors to obtain missing information. For this 2017 update we added one new trial involving 405 participants with uncomplicated acute respiratory infection. Overall, this review included 11 studies with a total of 3555 participants. These 11 studies involved acute respiratory infections including acute otitis media (three studies), streptococcal pharyngitis (three studies), cough (two studies), sore throat (one study), common cold (one study), and a variety of RTIs (one study). Five studies involved only children, two only adults, and four included both adults and children. Six studies were conducted in a primary care setting, three in paediatric clinics, and two in emergency departments.Studies were well reported, and appeared to be of moderate quality. Randomisation was not adequately described in two trials. Four trials blinded the outcomes assessor, and three included blinding of participants and doctors. We conducted meta-analysis for antibiotic use and patient satisfaction.We found no differences among delayed, immediate, and no prescribed antibiotics for clinical outcomes in the three studies that recruited participants with cough. For the outcome of fever with sore throat, three of the five studies favoured immediate antibiotics, and two found no difference. For the outcome of pain related to sore throat, two studies favoured immediate antibiotics, and three found no difference. One study compared delayed antibiotics with no antibiotic for sore throat, and found no difference in clinical outcomes.Three studies included participants with acute otitis media. Of the two studies with an immediate antibiotic arm, one study found no difference for fever, and the other study favoured immediate antibiotics for pain and malaise severity on Day 3. One study including participants with acute otitis media compared delayed antibiotics with no antibiotics and found no difference for pain and fever on Day 3.Two studies recruited participants with common cold. Neither study found differences for clinical outcomes between delayed and immediate antibiotic groups. One study favoured delayed antibiotics over no antibiotics for pain, fever, and cough duration (moderate quality evidence for all clinical outcomes - GRADE assessment).There were either no differences for adverse effects or results favoured delayed antibiotics over immediate antibiotics (low quality evidence - to GRADE assessment) with no significant differences in complication rates. Delayed antibiotics resulted in a significant reduction in antibiotic use compared to immediate antibiotics prescription (odds ratio (OR) 0.04, 95% confidence interval (CI) 0.03 to 0.05). However, a delayed antibiotic was more likely to result in reported antibiotic use than no antibiotics (OR 2.55, 95% CI 1.59 to 4.08) (moderate quality evidence - GRADE assessment).Patient satisfaction favoured delayed over no antibiotics (OR 1.49, 95% CI 1.08 to 2.06). There was no significant difference in patient satisfaction between delayed antibiotics and immediate antibiotics (OR 0.65, 95% CI 0.39 to 1.10) (moderate quality evidence - GRADE assessment).None of the included studies evaluated antibiotic resistance. For many clinical outcomes, there were no differences between prescribing strategies. Symptoms for acute otitis media and sore throat were modestly improved by immediate antibiotics compared with delayed antibiotics. There were no differences in complication rates. Delaying prescribing did not result in significantly different levels of patient satisfaction compared with immediate provision of antibiotics (86% versus 91%) (moderate quality evidence). However, delay was favoured over no antibiotics (87% versus 82%). Delayed antibiotics achieved lower rates of antibiotic use compared to immediate antibiotics (31% versus 93%) (moderate quality evidence). The strategy of no antibiotics further reduced antibiotic use compared to delaying prescription for antibiotics (14% versus 28%). Delayed antibiotics for people with acute respiratory infection reduced antibiotic use compared to immediate antibiotics, but was not shown to be different to no antibiotics in terms of symptom control and disease complications. Where clinicians feel it is safe not to prescribe antibiotics immediately for people with respiratory infections, no antibiotics with advice to return if symptoms do not resolve is likely to result in the least antibiotic use while maintaining similar patient satisfaction and clinical outcomes to delaying prescription of antibiotics. Where clinicians are not confident in using a no antibiotic strategy, a delayed antibiotics strategy may be an acceptable compromise in place of immediate prescribing to significantly reduce unnecessary antibiotic use for RTIs, and thereby reduce antibiotic resistance, while maintaining patient safety and satisfaction levels.Editorial note: As a living systematic review, this review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.


Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer.
Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.


If you want honesty, break some rules.
We've all heard, or perhaps even told, the "organizational lie"; We're customer centric; everyone's performance is above average; we're the darling of our industry, coming up with one innovation after another. That last one was true of Advanced Cardiovascular Systems (ACS) in the past, but not when Ginger Graham took over as CEO. From that first moment in 1993, Graham chose to tell the truth about ACS's situation--that R&D was practically at war with product development, yields were down, and customers were disgruntled. And ever since, she's seen the benefits of exploding organizational lies. Truth telling is something that's hard to argue with but difficult to do. And, indeed, ACS instituted some radical practices to create its culture of honesty. Every senior manager was assigned a coach from the ranks who regularly solicited feedback from everyone, high and low, about the executive's performance. To get the truth, though, ACS executives learned that they had to offer it up themselves--the whole truth about the company's financial state, its problems, and its triumphs. When they did, they found that, in return, they could ask their employees for help in solving the problems, and passive complainers became active partners in the company's fortunes. ACS management spreads the word about the virtues of honesty through vivid stories of corporate history and quirky rituals. Every quarter, it holds companywide meetings in which the faults of top managers are examined--to keep them honest and tough enough to go on telling the truth. In fact, in the process of openly owning up to problems and jointly fixing them with employees, the entire company grew more powerful, nimble, and tough-minded, able to respond quickly to change, both internal and external.


Understanding the relationships between spike rate and delta/gamma frequency bands of LFPs and EEGs using a local cortical network model.
Despite the widespread use of EEGs to measure the large-scale dynamics of the human brain, little is known on how the dynamics of EEGs relates to that of the underlying spike rates of cortical neurons. However, progress was made by recent neurophysiological experiments reporting that EEG delta-band phase and gamma-band amplitude reliably predict some complementary aspects of the time course of spikes of visual cortical neurons. To elucidate the mechanisms behind these findings, here we hypothesize that the EEG delta phase reflects shifts of local cortical excitability arising from slow fluctuations in the network input due to entrainment to sensory stimuli or to fluctuations in ongoing activity, and that the resulting local excitability fluctuations modulate both the spike rate and the engagement of excitatory-inhibitory loops producing gamma-band oscillations. We quantitatively tested these hypotheses by simulating a recurrent network of excitatory and inhibitory neurons stimulated with dynamic inputs presenting temporal regularities similar to that of thalamic responses during naturalistic visual stimulation and during spontaneous activity. The network model reproduced in detail the experimental relationships between spike rate and EEGs, and suggested that the complementariness of the prediction of spike rates obtained from EEG delta phase or gamma amplitude arises from nonlinearities in the engagement of excitatory-inhibitory loops and from temporal modulations in the amplitude of the network input, which respectively limit the predictability of spike rates from gamma amplitude or delta phase alone. The model suggested also ways to improve and extend current algorithms for online prediction of spike rates from EEGs.


Providing Doctors With High-Quality Information: An Updated Evaluation of Web-Based Point-of-Care Information Summaries.
The complexity of modern practice requires health professionals to be active information-seekers. Our aim was to review the quality and progress of point-of-care information summaries-Web-based medical compendia that are specifically designed to deliver pre-digested, rapidly accessible, comprehensive, and periodically updated information to health care providers. We aimed to evaluate product claims of being evidence-based. We updated our previous evaluations by searching Medline, Google, librarian association websites, and conference proceedings from August 2012 to December 2014. We included Web-based, regularly updated point-of-care information summaries with claims of being evidence-based. We extracted data on the general characteristics and content presentation of products, and we quantitatively assessed their breadth of disease coverage, editorial quality, and evidence-based methodology. We assessed potential relationships between these dimensions and compared them with our 2008 assessment. We screened 58 products; 26 met our inclusion criteria. Nearly a quarter (6/26, 23%) were newly identified in 2014. We accessed and analyzed 23 products for content presentation and quantitative dimensions. Most summaries were developed by major publishers in the United States and the United Kingdom; no products derived from low- and middle-income countries. The main target audience remained physicians, although nurses and physiotherapists were increasingly represented. Best Practice, Dynamed, and UptoDate scored the highest across all dimensions. The majority of products did not excel across all dimensions: we found only a moderate positive correlation between editorial quality and evidence-based methodology (r=.41, P=.0496). However, all dimensions improved from 2008: editorial quality (P=.01), evidence-based methodology (P=.015), and volume of diseases and medical conditions (P<.001). Medical and scientific publishers are investing substantial resources towards the development and maintenance of point-of-care summaries. The number of these products has increased since 2008 along with their quality. Best Practice, Dynamed, and UptoDate scored the highest across all dimensions, while others that were marketed as evidence-based were less reliable. Individuals and institutions should regularly assess the value of point-of-care summaries as their quality changes rapidly over time.


Herniation secondary to critical postcraniotomy cerebrospinal fluid hypovolemia.
Cerebrospinal fluid hypovolemia resulting in postural headaches is a well-known clinical entity, but severe forms of cerebrospinal fluid hypovolemia with altered mental status and signs of transtentorial herniation ("brain sag") have rarely been reported. This article describes the clinical features of brain sag after craniotomy in an attempt to increase recognition of this syndrome. Between April 2001 and January 2003, 220 consecutive patients with subarachnoid hemorrhage were prospectively enrolled in the Columbia Subarachnoid Hemorrhage Outcomes Project; 137 underwent craniotomy for aneurysm clipping. Among these patients, the diagnosis of brain sag was made when all three of the following criteria were present: clinical signs of transtentorial herniation, head computed tomographic scans revealing effacement of the basal cisterns with an oblong brainstem, and improvement of symptoms after placement of the patient in the Trendelenburg position (-15 to -30 degrees). For each patient, the symptoms, clinical course, and subsequent response to treatment were characterized. In addition, brainstem dimensions were measured on computed tomographic scans taken before, during, and after resolution of brain sag. A "sag ratio" was generated for these time points by dividing the maximum anteroposterior distance by the maximum bipeduncular distance. Eleven (8.0%) of 137 aneurysmal subarachnoid hemorrhage patients treated by craniotomy and an intraoperative spinal drain met the criteria for brain sag. Signs of transtentorial herniation developed most commonly between 2 and 4 days postoperatively. Pupillary asymmetry was noted in 10 (91.0%) of 11 patients, whereas the other patient demonstrated extensor posturing. The Trendelenburg position reversed the symptoms in all patients. The mean sag ratios before, during, and after resolution of brain sag were 0.91 +/- 0.03 (mean +/- standard error), 1.18 +/- 0.03, and 0.91 +/- 0.03, respectively. This represented a 30.9% elongation of the brainstem during sag (P < 0.001) and a 23.6% change back to baseline after resolution of the syndrome (P < 0.002). There was no significant difference between the presag and postsag ratios. Severe cerebrospinal fluid hypovolemia after craniotomy may produce a dramatic herniation syndrome that is completely reversed by the Trendelenburg position. Brain sag should be included in the differential diagnosis for acute postoperative clinical deterioration in this patient population.


Strain-Level Identification of Bacterial Tomato Pathogens Directly from Metagenomic Sequences.
Routine strain-level identification of plant pathogens directly from symptomatic tissue could significantly improve plant disease control and prevention. Here we tested the Oxford Nanopore Technologies (ONT) MinION sequencer for metagenomic sequencing of tomato plants either artificially inoculated with a known strain of the bacterial speck pathogen Pseudomonas syringae pv. tomato or collected in the field and showing bacterial spot symptoms caused by one of four Xanthomonas species. After species-level identification via ONT's WIMP software and the third-party tools Sourmash and MetaMaps, we used Sourmash and MetaMaps with a custom database of representative genomes of bacterial tomato pathogens to attempt strain-level identification. In parallel, each metagenome was assembled and the longest contigs were used as query with the genome-based microbial identification Web service LINbase. Both the read-based and assembly-based approaches correctly identified P. syringae pv. tomato strain T1 in the artificially inoculated samples. The pathogen strain in most field samples was identified as a member of Xanthomonas perforans group 2. This result was confirmed by whole genome sequencing of colonies isolated from one of the samples. Although in our case metagenome-based pathogen identification at the strain level was achieved, caution still must be exercised in interpreting strain-level results because of the challenges inherent to assigning reads to specific strains and the error rate of nanopore sequencing.


Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells.
Ablation of LGR5+ intestinal stem cells (ISCs) is associated with rapid restoration of the ISC compartment. Different intestinal crypt populations dedifferentiate to provide new ISCs, but the transcriptional and signaling trajectories that guide this process are unclear, and a large body of work suggests that quiescent "reserve" ISCs contribute to regeneration. By timing the interval between LGR5+ lineage tracing and lethal injury, we show that ISC regeneration is explained nearly completely by dedifferentiation, with contributions from absorptive and secretory progenitors. The ISC-restricted transcription factor ASCL2 confers measurable competitive advantage to resting ISCs and is essential to restore the ISC compartment. Regenerating cells re-express Ascl2 days before Lgr5, and single-cell RNA sequencing (scRNA-seq) analyses reveal transcriptional paths underlying dedifferentiation. ASCL2 target genes include the interleukin-11 (IL-11) receptor Il11ra1, and recombinant IL-11 enhances crypt cell regenerative potential. These findings reveal cell dedifferentiation as the principal means for ISC restoration and highlight an ASCL2-regulated signal that enables this adaptive response.


Novel Ag-doped glass frits for high-efficiency crystalline silicon solar cells.
Glass frits play an important role in the front contact electrodes of crystalline silicon (c-Si) solar cells. In this work, we developed a novel glass frit by doping Ag into a glass frit in the process of high-temperature synthesis. When the Ag paste including this novel glass frit was used as the front contact electrode of silicon solar cells, the conversion efficiency of poly-crystalline silicon (pc-Si) solar cells was improved by 1.9% compared to the glass frit without Ag. Through SEM characterisation and calculation of series resistance, we further found that the interface between Ag and Si was improved and the contact resistance of Ag and Si was greatly reduced, which were believed to be responsible for the improvement of solar cell performance. This work shows great guidance significance to develop novel and highly efficient commercial glass frits applied in solar cells in the future.


Evaluation of a behavior-centered design strategy for creating demand for oral PrEP among young women in Cape Town, South Africa.
There is an urgent need to find effective interventions that reduce young South African women's vulnerability to HIV, and pre-exposure prophylaxis (PrEP) is highly effective when taken consistently. As national programs in Africa launch PrEP programs for young women, it is critical to understand how to effectively create awareness, stimulate interest, and increase uptake of PrEP. Behavior-centered design (BCD) guided the development of a PrEP social marketing campaign for young women. Ethnographic observations, in-depth interviews, and focus-group discussions with young South African women informed the content and design of a 90-second PrEP demand creation video and two informational brochures. A short survey was administered to young women at their homes after watching a video to evaluate PrEP interest. Of 800 households with a 16-25-year-old female identified from a Cape Town township census, 320 women in these households viewed the video and completed a survey about the video and their interest in PrEP. In focus groups, young women from the township preferred local characters and messaging that was empowering, simple, and motivational. From the household survey of young women who viewed the video, most reported interest in learning more about PrEP (67.7% 'definitely interested' and 9.4% 'somewhat interested') and taking PrEP (56.4% 'definitely interested' and 12.5% 'somewhat interested'). Factors significantly associated with interest in taking PrEP were having a primary partner with whom they regularly have sex (80.0% vs. 65.2% without a primary partner; adjusted odds ratio (AOR)=3.1, 95% CI: 1.3, 7.0) and being in a sexual partnership for <6 months (86.8% vs. 68.5% for >12 months; AOR=3.0, 95% CI: 1.2, 7.3). A positively framed PrEP demand creation video generated high interest in PrEP among young South African women, particularly among women with a primary partner and a shorter-term relationship. Registration: NCT03142256; registered on 5 May 2017.


Maitake mushroom extracts ameliorate progressive hypertension and other chronic metabolic perturbations in aging female rats.
We assessed the ability of two commercially-available fractions labeled SX and D derived from the edible maitake mushroom to overcome many age-associated metabolic perturbations such as progressive, age-related elevation of blood pressure, over activity of the renin-angiotensin system (RAS), decreased insulin sensitivity, and inflammation in an in vivo laboratory model. We divided forty mature, female Sprague-Dawley rats (SD) into five groups of eight. SD ingested regular rat chow containing added sucrose (20% w/w). The groups received baseline diet alone (control) or baseline diet containing captopril, niacin-bound chromium, maitake fraction SX, or maitake fraction D. In addition to blood pressure readings, the following procedures were implemented: losartan and insulin challenges, evaluation of serum ACE activity, glucose tolerance testing, blood chemistries, LNAME challenge, and measurement of various circulating cytokines. We found that implementation of all test conditions stopped the gradual elevation of systolic blood pressure (SBP) in the SD over the four months of study, even reversing some of the previous elevation that occurred over time. In general, the treatment groups showed decreased activity of the RAS estimated by less lowering of SBP after losartan challenge and decreased serum ACE activity and were more sensitive to exogenous insulin challenge. TNFa levels decreased in all four test groups suggesting a lessening of the inflammatory state. We believe our data suggest that maitake mushroom fractions lessen age-related hypertension, at least in part, via effects on the RAS; enhance insulin sensitivity; and reduce some aspects of inflammation--actions that should lead to a longer, healthier life span.


Local lay rescuers with AEDs, alerted by text messages, contribute to early defibrillation in a Dutch out-of-hospital cardiac arrest dispatch system.
Public access defibrillation rarely reaches out-of-hospital cardiac arrest (OHCA) patients in residential areas. We developed a text message (TM) alert system, dispatching local lay rescuers (TM-responders). We analyzed the functioning of this system, focusing on response times and early defibrillation in relation to other responders. In July 2013, 14112 TM-responders and 1550 automated external defibrillators (AEDs) were registered in a database residing with the dispatch center of two regions of the Netherlands. TM-responders living <1000m radius of the patient received a TM to go to the patient directly, or were directed to retrieve an AED first. We analyzed 1536 OHCA patients where a defibrillator was connected from February 2010 until July 2013. Electrocardiograms from all defibrillators were analyzed for connection and defibrillation time. Of all OHCAs, the dispatcher activated the TM-alert system 893 times (58.1%). In 850 cases ≥1 TM-responder received a TM-alert and in 738 cases ≥1 AED was available. A TM-responder AED was connected in 184 of all OHCAs (12.0%), corresponding with 23.1% of all connected AEDs. Of all used TM-responder AEDs, 87.5% were used in residential areas, compared to 71.6% of all other defibrillators. TM-responders with AEDs defibrillated mean 2:39 (min:sec) earlier compared to emergency medical services (median interval 8:00 [25-75th percentile, 6:35-9:49] vs. 10:39 [25-75th percentile, 8:18-13:23], P<0.001). Of all shocking TM-responder AEDs, 10.5% delivered a shock ≤6min after call. A TM-alert system that includes local lay rescuers and AEDs contributes to earlier defibrillation in OHCA, particularly in residential areas.


Neutrophil chemoattractant production by cultured serotonin-stimulated bovine and human endothelial cells.
Recent studies have demonstrated that serotonin (5-HT) is avidly taken up and metabolized by vascular endothelial cells (EC) and have suggested that 5-HT may contribute to inflammatory responses. Because EC can produce neutrophil cytokines among their biologically active molecules, we hypothesized that the interaction of 5-HT and EC might cause production of such a cytokine. Using a modified Boyden chamber assay, we found that cultured bovine aortic (BA), bovine pulmonary arterial (BPA), and human umbilical vein (HUV) EC incubated with 5-HT produced a neutrophil chemoattractant (NCA). The NCA was predominantly chemotactic, was not stored in an active form, appeared within 5 min of incubation with 5-HT, and required de novo protein synthesis for its appearance. The mechanism of NCA production was different in the three types of EC examined. Elaboration of NCA and BAEC and HUVEC was apparently mediated by 5-HT1 receptors and did not require uptake of 5-HT, whereas its elaboration from BPAEC required 5-HT uptake and was apparently mediated by 5-HT2 receptors. Incubation with three different lipoxygenase inhibitors blocked production of NCA, whereas incubation with a cyclooxygenase inhibitor did not. Further characterization of the NCA demonstrated that it was a mixture of several different chemotactic lipids and was distinct from other lipid or phospholipid neutrophil chemoattractants. These studies suggest that the interaction of the platelet-release product, 5-HT, with the adjacent endothelium results in the production of a chemoattractant that could affect neutrophil accumulation at sites of inflammation.


Eight-year follow-up of olanzapine therapy in a previous treatment-refractory schizophrenic patient: a case report.
The introduction of atypical antipsychotic drugs during the 1990s represented a great step forward in the treatment of schizophrenia and other psychoses. These drugs might more effectively prevent relapse because of their effectiveness against a wider range of schizophrenic symptoms, as well as their improved tolerability, which leads to improved medication compliance. Olanzapine, a thienobenzodiazapine, is an antipsychotic drug with high affinity for the serotonergic receptors 5-HT 2 and 5-HT 6 and high affinity for dopaminergic receptors, mainly D2, D3 and D4, and with a lower propensity to cause extrapyramidal symptoms or increasing prolactin levels. The long-term efficacy and safety of olanzapine for treating treatment-refractory schizophrenia is still being investigated. The authors present a case of a 43-year-old man suffering from chronic treatment-resistant schizophrenia with both positive and negative symptoms, who was successfully treated with olanzapine for 8 years. (Int J Psych Clin Pract 2002; 6: 211-214 ).


Design of a combinatorial DNA microarray for protein-DNA interaction studies.
Discovery of precise specificity of transcription factors is an important step on the way to understanding the complex mechanisms of gene regulation in eukaryotes. Recently, double-stranded protein-binding microarrays were developed as a potentially scalable approach to tackle transcription factor binding site identification. Here we present an algorithmic approach to experimental design of a microarray that allows for testing full specificity of a transcription factor binding to all possible DNA binding sites of a given length, with optimally efficient use of the array. This design is universal, works for any factor that binds a sequence motif and is not species-specific. Furthermore, simulation results show that data produced with the designed arrays is easier to analyze and would result in more precise identification of binding sites. In this study, we present a design of a double stranded DNA microarray for protein-DNA interaction studies and show that our algorithm allows optimally efficient use of the arrays for this purpose. We believe such a design will prove useful for transcription factor binding site identification and other biological problems.


Integration of Elicitors and Less-Susceptible Hybrids for the Control of Powdery Mildew in Organic Tomato Crops.
Powdery mildew is a serious economic problem in Mediterranean tomato production. The disease is currently controlled by fungicides (especially sulfur) in both conventional and organic production. Four factorial greenhouse experiments were conducted in successive cropping seasons (autumn 2005, autumn 2006, spring 2006, and spring 2007) to assess the main and combined effects of (i) a less-susceptible hybrid ('Elpida'), (ii) chitin soil amendment, or (iii) Milsana or chitosan elicitor foliar treatments on the severity of powdery mildew and crop performance. Analysis of variance revealed significant effects of cropping season on disease severity and crop yield. All control practices reduced disease severity; reductions of approximately 40, 30, 15, and 15% were achieved by Milsana foliar treatment, the use of a less-susceptible hybrid, chitosan foliar treatment, and chitin soil amendment, respectively. In the season with the highest disease pressure, higher yields were obtained with the less-susceptible hybrid Elpida whereas, in the three seasons with no or low disease pressure, the use of the more susceptible hybrid 'Bison' produced higher yields. Milsana and sulfur treatments did not significantly affect yield (yields were slightly lower compared with untreated control plants) and, therefore, their use cannot be recommended based on the results obtained.


Generalization and transfer of contextual cues in motor learning.
We continuously adapt our movements in daily life, forming new internal models whenever necessary and updating existing ones. Recent work has suggested that this flexibility is enabled via sensorimotor cues, serving to access the correct internal model whenever necessary and keeping new models apart from previous ones. While research to date has mainly focused on identifying the nature of such cue representations, here we investigated whether and how these cue representations generalize, interfere, and transfer within and across effector systems. Subjects were trained to make two-stage reaching movements: a premovement that served as a cue, followed by a targeted movement that was perturbed by one of two opposite curl force fields. The direction of the premovement was uniquely coupled to the direction of the ensuing force field, enabling simultaneous learning of the two respective internal models. After training, generalization of the two premovement cues' representations was tested at untrained premovement directions, within both the trained and untrained hand. We show that the individual premovement representations generalize in a Gaussian-like pattern around the trained premovement direction. When the force fields are of unequal strengths, the cue-dependent generalization skews toward the strongest field. Furthermore, generalization patterns transfer to the nontrained hand, in an extrinsic reference frame. We conclude that contextual cues do not serve as discrete switches between multiple internal models. Instead, their generalization suggests a weighted contribution of the associated internal models based on the angular separation from the trained cues to the net motor output.


Quality of Evidence-Based Guidelines for Transfusion of Red Blood Cells and Plasma: A Systematic Review.
Many transfusion guidelines are available, but little appraisal of their quality has been undertaken. The quality of guidelines may potentially influence adoption. Our aim was to determine the quality of evidence-based transfusion guidelines (EBG) for red cells and plasma, using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument, and assess duplication and consistency of recommendations. MEDLINE and EMBASE were systematically searched for EBG from 2005 to June 3, 2016. Citations were reviewed for inclusion in duplicate. A guideline was included if it had a specified clinical question, described a systematic search strategy, included critical appraisal of the literature and a description of how recommendations were developed. Four to six physicians used AGREE II to appraise each guideline. Median and scaled scores were calculated, with each item scored on a scale of one to seven, seven representing the highest score. Of 6174 citations, 30 guidelines met inclusion criteria. Twenty six guidelines had recommendations for red cells and 18 included recommendations for plasma use. The median score, the scaled score and the interquartile range of the scaled score were: scope and purpose: median score 5, scaled score 60%, IQR (49-74%); stakeholder involvement 4, 43%, (33-49%); rigor of development 4, 41%, (19-59%); clarity of presentation 5, 69%, (52-81%); applicability 1, 16%, (9-23%); editorial independence 3, 43%, (20-58%). Sixteen guidelines were evaluated to have a scaled domain score of 50% or less. Variations in recommendations were found for the use of hemoglobin triggers for red cell transfusion in patients with acute coronary syndromes and for plasma use for patients with bleeding. Our findings document, limited rigor in guideline development and duplication and inconsistencies in recommendations for the same topic. The process of developing guidelines for red cells and plasma transfusion can be enhanced to improve implementation.


The overlap between bronchiectasis and chronic airway diseases: state of the art and future directions.
Bronchiectasis is a clinical and radiological diagnosis associated with cough, sputum production and recurrent respiratory infections. The clinical presentation inevitably overlaps with other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). In addition, 4-72% of patients with severe COPD are found to have radiological bronchiectasis on computed tomography, with similar frequencies (20-30%) now being reported in cohorts with severe or uncontrolled asthma. Co-diagnosis of bronchiectasis with another airway disease is associated with increased lung inflammation, frequent exacerbations, worse lung function and higher mortality. In addition, many patients with all three disorders have chronic rhinosinusitis and upper airway disease, resulting in a complex "mixed airway" phenotype.The management of asthma, bronchiectasis, COPD and upper airway diseases has traditionally been outlined in separate guidelines for each individual disorder. Recognition that the majority of patients have one or more overlapping pathologies requires that we re-evaluate how we treat airway disease. The concept of treatable traits promotes a holistic, pathophysiology-based approach to treatment rather than a syndromic approach and may be more appropriate for patients with overlapping features.Here, we review the current clinical definition, diagnosis, management and future directions for the overlap between bronchiectasis and other airway diseases.


Integrating perioperative chemotherapy into the treatment of muscle-invasive bladder cancer: strategy versus reality.
Since the initial report in 2003 of the Intergroup-0080 trial confirming benefit of combined neoadjuvant M-VAC (methotrexate, vinblastine, adriablastine, and cisplatin) chemotherapy and cystectomy in the treatment of muscle-invasive bladder cancer, debate has continued in the literature as to the relative risk/benefits of integrating perioperative chemotherapy into the care of patients, especially in those with organ-confined, muscle-invasive, node-negative disease in whom the benefit may be less. Because of the inaccuracies of clinical staging, the potential morbidity related to M-VAC chemotherapy, a 70% cure rate in pT2No disease with surgery alone, and only a modest (5%) improvement in absolute overall survival with combined therapy, many favor limiting chemotherapy to patients with a pathologic stage of pT3 or greater or node-positive disease. This philosophy was also reflected in the 2008 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Bladder Cancer, in which neoadjuvant chemotherapy for clinical T2 disease versus adjuvant therapy based on pathologic risks is only "considered." Additionally, a recent study looking at the perioperative integration of chemotherapy for stage III bladder cancer in the United States using the National Cancer Data Base showed that only 11.6% of patients underwent any perioperative chemotherapy, with most in the adjuvant setting. These findings indicate that despite randomized trial data showing survival benefit for perioperative chemotherapy, and the current guidelines for therapy supporting those findings, chemotherapy is not being integrated well into the care of patients with muscle-invasive bladder cancer, even in those who, experts agree, have the most potential for benefit.


Faculty and student assessment of and experience with incivility in nursing education.
Academic incivility is a significant problem and reports of discord on college campuses underscore the need for addressing uncivil behaviors in a forthright manner. In this study, 504 respondents from 41 states--194 nursing faculty, 306 nursing students, and 4 who did not specify their status--completed the Incivility in Nursing Education survey. The most frequently cited uncivil student behaviors included holding distracting conversations, using computers unrelated to class, and demanding make-up examinations and grade changes. The uncivil student behaviors occurring most frequently were arriving late for class, holding distracting conversations, and being unprepared. The uncivil faculty behaviors most frequently cited included making condescending remarks, making rude gestures or comments, and exerting superiority over others. The uncivil faculty behaviors occurring most frequently included ineffective teaching methods, arriving late for scheduled activities, and deviating from the syllabus and changing class assignments. Student and faculty uncivil behaviors were viewed similarly by both groups.


Defining New Pathways to Manage the Ongoing Emergence of Bat Rabies in Latin America.
Rabies transmitted by common vampire bats (Desmodus rotundus) has been known since the early 1900s but continues to expand geographically and in the range of species and environments affected. In this review, we present current knowledge of the epidemiology and management of rabies in D. rotundus and argue that it can be reasonably considered an emerging public health threat. We identify knowledge gaps related to the landscape determinants of the bat reservoir, reduction in bites on humans and livestock, and social barriers to prevention. We discuss how new technologies including autonomously-spreading vaccines and reproductive suppressants targeting bats might manage both rabies and undesirable growth of D. rotundus populations. Finally, we highlight widespread under-reporting of human and animal mortality and the scarcity of studies that quantify the efficacy of control measures such as bat culling. Collaborations between researchers and managers will be crucial to implement the next generation of rabies management in Latin America.


Core-shell colloidal particles with dynamically tunable scattering properties.
We design polystyrene-poly(N'-isopropylacrylamide-co-acrylic acid) core-shell particles that exhibit dynamically tunable scattering. We show that under normal solvent conditions the shell is nearly index-matched to pure water, and the particle scattering is dominated by Rayleigh scattering from the core. As the temperature or salt concentration increases, both the scattering cross-section and the forward scattering increase, characteristic of Mie scatterers. The magnitude of the change in the scattering cross-section and scattering anisotropy can be controlled through the solvent conditions and the size of the core. Such particles may find use as optical switches or optical filters with tunable opacity.


Defining Usual Care in Clinical Trials.
Pragmatic trials occur within the complexity of real-world care delivery, and when effective, contribute to more rapid translation into practice because of their greater generalizability. Research with older adults is complex when participants have chronic conditions and multiple comorbidities. Often pragmatic trials introduce a novel intervention and try to determine whether it offers a benefit beyond the usual or routine care provided. Researchers commonly focus attention on describing the intervention, yet the comparator condition of usual or routine care can be anything but standard, reducing the effect size of the intervention and introducing threats to the overall validity of the study. The current article describes clinical trial guidelines, then illustrates the complexity of characterizing usual care for interventions addressing type 2 diabetes. The authors provide recommendations for improving description of usual care and discuss implications for gerontological nursing research. [Research in Gerontological Nursing, 13(3), 125-129.].


Predictors of family functioning after traumatic brain injury in children and adolescents.
To assess factors predictive of family outcome in the first 2 years after traumatic brain injury (TBI) in children and adolescents. Subjects were children aged 6 to 14 at the time they were hospitalized after TBI. The study used a prospective follow-up design. Assessments of preinjury factors (psychiatric family functioning, and family life events), injury factors (severity of injury), and postinjury factors (coping and development of a psychiatric disorder, never before present, i.e., "novel") were conducted using standard clinical scales. The outcome measure was family function as assessed with standardized family functioning interviews (at 12 and 24 months after TBI) and primary caretaker self-report questionnaires (at 3 and 6 months after TBI). Fifty subjects enrolled, and the analyses focused on 37, 41, 43, and 42 subjects assessed at the 3-, 6-, 12-, and 24-month follow-up evaluations, respectively. The strongest influences on family functioning after childhood TBI are preinjury family functioning, the development of a "novel" psychiatric disorder in the child, and preinjury family life events or stressors. These data suggest that there are families, identifiable through clinical assessment, at increased risk for family dysfunction after a child's TBI. Early identification and treatment of the child's psychopathology and family dysfunction may attenuate the associated morbidity.


Detailed Magnetic Resonance Imaging (MRI) Analysis in Infantile Spasms.
To evaluate initial magnetic resonance imaging (MRI) abnormalities in infantile spasms, correlate them to clinical characteristics, and describe repeat imaging findings. A retrospective review of infantile spasm patients was conducted, classifying abnormal MRI into developmental, acquired, and nonspecific subgroups. MRIs were abnormal in 52 of 71 infantile spasm patients (23 developmental, 23 acquired, and 6 nonspecific) with no correlation to the clinical infantile spasm characteristics. Both developmental and acquired subgroups exhibited cortical gray and/or white matter abnormalities. Additional abnormalities of deep gray structures, brain stem, callosum, and volume loss occurred in the structural acquired subgroup. Repeat MRI showed better definition of the extent of existing malformations. In structural infantile spasms, developmental/acquired subgroups showed differences in pattern of MRI abnormalities but did not correlate with clinical characteristics.


Dietary intake of vitamin K is inversely associated with mortality risk.
Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aim of the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95% CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639.


Infection time and density influence the response of sorghum to the parasitic angiosperm Striga hermonthica.
Two cultivars of sorghum (CSH-1 and Ochuti) were grown in the presence and absence of the root hemiparasite Striga hermonthica in uniform conditions in the field in Kenya, Africa. S. hermonthica had a marked influence on growth and photosynthesis of 'CSH-1'; however, 'Ochuti' showed a less severe response to infection and tolerance of the parasite. The variation in genotype response might be partly explained by later attachment of the parasite and a lower level of infection. Laboratory studies were used to determine the importance of both variables in determining host response to infection. Early infection by S. hermonthica had a more negative effect on the host than late infection. The level of parasite biomass supported by the host also influenced host productivity but the relationship was nonlinear. Low degrees of parasite infection had a proportionately much greater effect on host grain weight than at greater parasite loading. Early infection of 'Ochuti' in laboratory conditions resulted in lower stem dry weight than in uninfected plants but not in smaller total plant biomass or lower rates of photosynthesis. In conclusion, the time of parasite attachment affected host performance and might explain much of the variation in host sensitivity both within and between studies. The level of parasite infection affected host performance to a lesser extent. In addition, late attachment and low levels of infection might have implications for control management strategies.


Metabolomics in chronic lung diseases.
Chronic lung diseases represent a significant global burden. Their increasing incidence and complexity render a comprehensive, multidisciplinary and personalized approach to each patient, critically important. Most recently, unique biochemical pathways and disease markers have been identified through large-scale metabolomic studies. Metabolomics is the study of metabolic pathways and the measurement of unique biomolecules in a living system. Analysing samples from different compartments such as bronchoalveolar lavage fluid (BALF) and plasma has proven useful for the characterization of a number of pathological conditions and offers promise as a clinical tool. For example, several studies using mass spectrometry (MS) have shown alterations in the sphingolipid metabolism of chronic obstructive pulmonary disease (COPD) sufferers. In this article, we present a practical review of the application of metabolomics to the study of chronic lung diseases (CLD): COPD, idiopathic pulmonary fibrosis (IPF) and asthma. The insights, which the analytical strategies employed in metabolomics, have provided to the dissection of the biochemistry of CLD and future clinical biomarkers are explored.


[Fluoroquinolones: Non-antibacterial properties].
Fluoroquinolones are a class of well-established chemotherapeutic agents with a potent biological activity being the structure of 4-quinolone-3-carboxilic acids privileged because it contains different sites for functionalization allowing expand its use in clinical practice for their antifungal, antiviral and anticancer activities. Quinolones structural changes have resulted in a first, second, third and fourth generation of drugs so it is advisable to continue modifying existing structures in new ways to generate compounds with desirable biological and pharmacological properties.


Improving residual feed intake of mule progeny of Muscovy ducks: genetic parameters and responses to selection with emphasis on carcass composition and fatty liver quality.
In France, about 95% of the fatty liver production comes from mule ducks, an infertile hybrid cross between female common ducks (Anas platyrhynchos) and Muscovy drakes (Cairina moschata). As a hybrid, genetic improvement of the performance of mule ducks is achieved by selection of the parental populations. Feed represents two-thirds of the total costs of duck production; thus, the breeders' main concern is to improve the birds' feed efficiency without impairing their capacity to be overfed after the growing period. To obtain insight into this economically important trait, we designed a divergent selection experiment for Muscovy sires on the basis of the residual feed intake (RFI) of their male mule progeny. Residual feed intake represents the fraction of feed intake that cannot be explained by maintenance and production requirements. Data comprised records from generations 0 to 2 with 227 Muscovy sires of 2,016 mule ducks. Growth and fat deposition were measured individually for all mule ducks. Half-sib mule ducks were placed together in 1 small pen, and the feed consumption was recorded for each pen; all half-sibs therefore had the same feed intake estimates. Heritability of RFI was high (0.83 ± 0.42), and after 2 generations of selection, the differences between lines in terms of RFI (contrast of 9.13 g/d, representing 0.76 phenotypic standard deviation; P < 0.0001) and feed conversion ratio (contrast of 0.08, representing 0.28 phenotypic standard deviation; P = 0.0003) were marked. In regard to carcass traits, the low-RFI line (high-efficiency animals) had heavier legs (476 vs. 463 g; P < 0.0001) and magret muscles (268 vs. 262 g; P = 0.001) than the high-RFI line (low-efficiency animals). No differences were observed for either the liver weight or the melting rate between the 2 lines (P > 0.46). Selection on RFI thus improves the feed efficiency of animals without impairing their capacity to produce fatty liver.