A randomized phase II study of cetuximab every 2 weeks at either 500 or 750 mg/m2 for patients with recurrent or metastatic head and neck squamous cell cancer.
Cetuximab is typically administered on a weekly schedule for patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC). This study explores cetuximab administered every 2 weeks (q2w). In this multicenter randomized prospective phase II study, eligible patients (≤2 prior cytotoxic chemotherapy regimens for recurrent or metastatic disease; ECOG performance status ≤2) were randomized to receive cetuximab q2w at 500 mg/m(2) (Group A) or 750 mg/m(2) (Group B). The primary end point was response rate (RECIST 1.0). Sixty-one patients were enrolled: 35 in Group A and 26 in Group B, which was closed early for lack of efficacy. Confirmed partial response rates were 11% for Group A (4/35) and 8% for Group B (2/26) according to intention to treat analysis. Partial responses occurred only among patients whose primary tumors were in the oral cavity or larynx. Median progression-free survival (PFS) and median overall survival (OS) were similar for both groups (PFS, 2.2 and 2.0 months; OS, 7.0 and 9.4 months; Groups A and B, respectively). The most common cetuximab-related adverse events (all grades) among treated subjects included rash, fatigue, and hypomagnesemia. Cetuximab, 500 mg/m(2), q2w achieves similar efficacy as conventional dosing for patients with recurrent or metastatic HNSCC. Escalating the dose to 750 mg/m(2) q2w offers no obvious therapeutic advantage.


Heterogeneous and Flexible Transmission of mcr-1 in Hospital-Associated Escherichia coli.
The recent emergence of a transferable colistin resistance mechanism, MCR-1, has gained global attention because of its threat to clinical treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, the possible transmission route of mcr-1 among Enterobacteriaceae species in clinical settings is largely unknown. Here, we present a comprehensive genomic analysis of Escherichia coli isolates collected in a hospital in Hangzhou, China. We found that mcr-1-carrying isolates from clinical infections and feces of inpatients and healthy volunteers were genetically diverse and were not closely related phylogenetically, suggesting that clonal expansion is not involved in the spread of mcr-1 The mcr-1 gene was found on either chromosomes or plasmids, but in most of the E. coli isolates, mcr-1 was carried on plasmids. The genetic context of the plasmids showed considerable diversity as evidenced by the different functional insertion sequence (IS) elements, toxin-antitoxin (TA) systems, heavy metal resistance determinants, and Rep proteins of broad-host-range plasmids. Additionally, the genomic analysis revealed nosocomial transmission of mcr-1 and the coexistence of mcr-1 with other genes encoding β-lactamases and fluoroquinolone resistance in the E. coli isolates. These findings indicate that mcr-1 is heterogeneously disseminated in both commensal and pathogenic strains of E. coli, suggest the high flexibility of this gene in its association with diverse genetic backgrounds of the hosts, and provide new insights into the genome epidemiology of mcr-1 among hospital-associated E. coli strains.IMPORTANCE Colistin represents one of the very few available drugs for treating infections caused by extensively multidrug-resistant Gram-negative bacteria. The recently emergent mcr-1 colistin resistance gene threatens the clinical utility of colistin and has gained global attention. How mcr-1 spreads in hospital settings remains unknown and was investigated by whole-genome sequencing of mcr-1-carrying Escherichia coli in this study. The findings revealed extraordinary flexibility of mcr-1 in its spread among genetically diverse E. coli hosts and plasmids, nosocomial transmission of mcr-1-carrying E. coli, and the continuous emergence of novel Inc types of plasmids carrying mcr-1 and new mcr-1 variants. Additionally, mcr-1 was found to be frequently associated with other genes encoding β-lactams and fluoroquinolone resistance. These findings provide important information on the transmission and epidemiology of mcr-1 and are of significant public health importance as the information is expected to facilitate the control of this significant antibiotic resistance threat.


Treatment patterns and survival in patients with ALK-positive non-small-cell lung cancer: a Canadian retrospective study.
Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase (ALK)-positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK+ nsclc in Canada. In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK+ nsclc were reviewed. Demographic and clinical characteristics, treatments, and outcomes data were abstracted. Analyses focused on patients who discontinued crizotinib treatment. Of the 97 patients included, 9 were crizotinib-naïve, and 39 were still receiving crizotinib at study end. The 49 patients who discontinued crizotinib treatment were included in the analysis. Of those 49 patients, 43% received ceritinib at any time, 20% subsequently received systemic chemotherapy only (but never ceritinib), and 37% received no further treatment or died before receiving additional treatment. Median overall survival from crizotinib discontinuation was shorter in patients who did not receive ceritinib than in those who received ceritinib (1.7 months vs. 20.4 months, p < 0.001). In a multivariable analysis, factors associated with poorer survival included lack of additional therapies (particularly ceritinib), male sex, and younger age, but not smoking status; patients of Asian ethnicity showed a nonsignificant trend toward improved survival. A substantial proportion of patients with ALK+ nsclc received no further treatment or died before receiving additional treatment after crizotinib. Treatment with systemic agents was associated with improved survival, with ceritinib use being associated with the longest survival.


Effect of backbone chemistry on hybridization thermodynamics of oligonucleic acids: a coarse-grained molecular dynamics simulation study.
In this paper we study how varying oligonucleic acid backbone chemistry affects the hybridization/melting thermodynamics of oligonucleic acids. We first describe the coarse-grained (CG) model with tunable parameters that we developed to enable the study of both naturally occurring oligonucleic acids, such as DNA, and their chemically-modified analogues, such as peptide nucleic acids (PNAs) and locked nucleic acids (LNAs). The DNA melting curves obtained using such a CG model and molecular dynamics simulations in an implicit solvent and with explicit ions match with the melting curves obtained using the empirical nearest-neighbor models. We use these CG simulations to then elucidate the effect of backbone flexibility, charge, and nucleobase spacing along the backbone on the melting curves, potential energy and conformational entropy change upon hybridization and base-pair hydrogen bond residence time. We find that increasing backbone flexibility decreases duplex thermal stability and melting temperature mainly due to increased conformational entropy loss upon hybridization. Removing charges from the backbone enhances duplex thermal stability due to the elimination of electrostatic repulsion and as a result a larger energetic gain upon hybridization. Lastly, increasing nucleobase spacing decreases duplex thermal stability due to decreasing stacking interactions that are important for duplex stability.


Systematic review of ultrasound visual biofeedback in intervention for speech sound disorders.
As cost and access barriers to ultrasound technology have decreased, interest in using ultrasound visual biofeedback (U-VBF) as a tool for remediating speech sound disorders (SSD) has increased. A growing body of research has investigated U-VBF in intervention for developmental SSD; however, diversity in study design, participant characteristics, clinical methods and outcomes complicate the interpretation of this literature. Thus, there is a need for a synthesis and review of the evidence base for using U-VBF in intervention for SSD. To synthesise and evaluate the research evidence for U-VBF in intervention for developmental SSD. A systematic review was conducted. Eight electronic databases were searched for peer-reviewed articles published before 2018. Details about study design, participants, intervention procedures, service delivery, intervention intensity and outcomes were extracted from each study that met the inclusion criteria. The included studies were rated using both a critical appraisal tool and for their reporting of intervention detail. Twenty-eight papers, comprising 29 studies, met the inclusion criteria. The most common research design was single-case experimental design (44.8% of studies). The studies included between one and 13 participants (mean = 4.1) who had a mean age of approximately 11 years (range = 4;0-27 years). Within the research evidence, U-VBF intervention was typically provided as part of, or as an adjunct to, other articulatory-based therapy approaches. A range of lingual sounds were targeted in intervention, with 80.6% of participants across all reviewed studies receiving intervention targeting rhotics. Outcomes following therapy were generally positive with the majority of studies reporting that U-VBF facilitated acquisition of targets, with effect sizes ranging from no effect to a large effect. Difficulties with generalisation were observed for some participants. Most studies (79.3%) were categorised as efficacy rather than effectiveness studies and represented lower levels of evidence. Overall, the reviewed studies scored more highly on measures of external validity than internal validity. The evidence base for U-VBF is developing; however, most studies used small sample sizes and lower strength designs. Current evidence indicates that U-VBF may be an effective adjunct to intervention for some individuals whose speech errors persist despite previous intervention. The results of this systematic review underscore the need for more high-quality and large-scale research exploring the use of this intervention in both controlled and community contexts.


A biome-scale assessment of the impact of invasive alien plants on ecosystem services in South Africa.
This paper reports an assessment of the current and potential impacts of invasive alien plants on selected ecosystem services in South Africa. We used data on the current and potential future distribution of 56 invasive alien plant species to estimate their impact on four services (surface water runoff, groundwater recharge, livestock production and biodiversity) in five terrestrial biomes. The estimated reductions in surface water runoff as a result of current invasions were >3000 million m(3) (about 7% of the national total), most of which is from the fynbos (shrubland) and grassland biomes; the potential reductions would be more than eight times greater if invasive alien plants were to occupy the full extent of their potential range. Impacts on groundwater recharge would be less severe, potentially amounting to approximately 1.5% of the estimated maximum reductions in surface water runoff. Reductions in grazing capacity as a result of current levels of invasion amounted to just over 1% of the potential number of livestock that could be supported. However, future impacts could increase to 71%. A 'biodiversity intactness index' (the remaining proportion of pre-modern populations) ranged from 89% to 71% for the five biomes. With the exception of the fynbos biome, current invasions have almost no impact on biodiversity intactness. Under future levels of invasion, however, these intactness values decrease to around 30% for the savanna, fynbos and grassland biomes, but to even lower values (13% and 4%) for the two karoo biomes. Thus, while the current impacts of invasive alien plants are relatively low (with the exception of those on surface water runoff), the future impacts could be very high. While the errors in these estimates are likely to be substantial, the predicted impacts are sufficiently large to suggest that there is serious cause for concern.


Systematic mistakes are likely in bounded optimal decision-making systems.
Systematic mistakes can be distinguished from other types of mistakes in that they are repeatable and predictable within a given organism, and are not due to uncertainty or lack of information. Here we provide a mathematical definition for the concept of systematic mistakes, which captures the way this concept has been used in the behavioral sciences. We also provide an analytical model of information processing networks that are made of large numbers of components, in analogy to the brain being made of a large number of neurons. We show that, for almost all behavioral tasks, and for a wide range of limitations on the computational complexity of the decision-making network, the best possible decision-makers will make systematic mistakes. This result, together with available empirical evidence, suggests that violations of rationality in humans and animals are consistent with natural selection, as the latter operates under constraints.


Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection.
Several respiratory viruses, including influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV), produce more severe disease in the elderly, yet the molecular mechanisms governing age-related susceptibility remain poorly studied. Advanced age was significantly associated with increased SARS-related deaths, primarily due to the onset of early- and late-stage acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways by which SARS-CoV infection induces changes in the host response, leading to death.


Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), harboring spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) mutations, exhibit reduced in vitro susceptibility to convalescent-phase serum, commercial antibody cocktails, and vaccine neutralization and have been associated with reinfections. The accumulation of these mutations could be the consequence of intrahost viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on steroids and convalescent plasma therapy and identify the emergence of multiple NTD and RBD mutations. SARS-CoV-2 genomes from the first swab (day 0) and from three tracheal aspirates (days 7, 21, and 27) were compared at the sequence level. We identified a mixed viral population with five different S protein mutations (141 to 144 deletion, 243 to 244 deletion, E484K, Q493K, and Q493R) at the NTD or RBD region from the second tracheal aspirate sample (day 21) and a predominance of the S protein 141 to 144 LGVY deletion and E484K mutant on day 27. The neutralizing antibodies against various S protein lentiviral pseudovirus mutants, as well as the anti-SARS-CoV-2 total Ig and IgG, showed "U" shape dynamics, in support of the endogenous development of neutralizing antibodies. The patient's compromised immune status, the antirejection regiment, convalescent plasma treatment, and the development of neutralizing antibodies may have resulted in unique selective pressures on the intrahost genomic evolution, and this observation supports the hypotheses that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune escape mutants. IMPORTANCE Over a year of the COVID-19 pandemic, distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages have arisen in multiple geographic areas around the world. SARS-CoV-2 variants of concern (VOCs), i.e., B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), harboring mutations and/or deletions in spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) regions showed evidence of increased transmissibility and disease severity and possible reduced vaccine efficacy. In this study, we report the emergence of five different NTD and RBD mutations in an uncommon SARS-CoV-2 B.1.369 lineage from an immunosuppressed patient undergoing steroid and convalescent plasma therapy. The observation highlighted that VOCs can independently arise in immunocompromised populations undergoing anti-SARS-CoV-2 therapy, and enhanced measures will be required to reduce the transmission.


Architecture of DNA elements mediating ARF transcription factor binding and auxin-responsive gene expression in Arabidopsis.
The hormone auxin controls many aspects of the plant life cycle by regulating the expression of thousands of genes. The transcriptional output of the nuclear auxin signaling pathway is determined by the activity of AUXIN RESPONSE transcription FACTORs (ARFs), through their binding to cis-regulatory elements in auxin-responsive genes. Crystal structures, in vitro, and heterologous studies have fueled a model in which ARF dimers bind with high affinity to distinctly spaced repeats of canonical AuxRE motifs. However, the relevance of this "caliper" model, and the mechanisms underlying the binding affinities in vivo, have remained elusive. Here we biochemically and functionally interrogate modes of ARF-DNA interaction. We show that a single additional hydrogen bond in Arabidopsis ARF1 confers high-affinity binding to individual DNA sites. We demonstrate the importance of AuxRE cooperativity within repeats in the Arabidopsis TMO5 and IAA11 promoters in vivo. Meta-analysis of transcriptomes further reveals strong genome-wide association of auxin response with both inverted (IR) and direct (DR) AuxRE repeats, which we experimentally validated. The association of these elements with auxin-induced up-regulation (DR and IR) or down-regulation (IR) was correlated with differential binding affinities of A-class and B-class ARFs, respectively, suggesting a mechanistic basis for the distinct activity of these repeats. Our results support the relevance of high-affinity binding of ARF transcription factors to uniquely spaced DNA elements in vivo, and suggest that differential binding affinities of ARF subfamilies underlie diversity in cis-element function.


The contact-system dependent plasminogen activator from human plasma: identification and characterization.
Apart from tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), a third PA appears to occur in human plasma. Its activity is initiated when appropriate triggers of the contact system are added, and the activation depends on the presence of factor XII and prekallikrein in plasma. The activity of this, so-called, contact-system dependent PA accounts for 30% of the PA activity in the dextran sulphate euglobulin fraction of plasma and was shown not to be an intrinsic property of one of the contact-system components, nor could it be inhibited by inhibitory antibodies against t-PA or u-PA. We have succeeded in identifying this third PA in dextran sulphate euglobulin fractions of human plasma. Its smallest unit (SDS-PAGE) is an inactive 110 kDa single-chain polypeptide which upon activation of the contact system is converted to a cleaved, disulphide-bridged molecule with PA activity. The native form, presumably, is an oligomer, since the apparent Mr on gel-chromatography is 600,000. The IEP is 4.8, much lower than that of t-PA and u-PA. Although the active 110 kDa polypeptide cannot be inhibited by anti-u-PA, it yet comprises a 37 kDa piece with some u-PA related antigenic determinants. However, these determinants are in a latent or cryptic form, only detectable after denaturation by SDS. The 110 kDa polypeptide is evidently not a dimer of 55 kDa u-PA or a complex of u-PA with an inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)


Food Containing Bioactive Flavonoids and Other Phenolic or Sulfur Phytochemicals With Antiviral Effect: Can We Design a Promising Diet Against COVID-19?
Since in late 2019, when the coronavirus 2 (SARS-CoV-2) pathogen of coronavirus disease 2019 (COVID-19) started to spread all over the world, causing the awful global pandemic we are still experiencing, an impressive number of biologists, infectious disease scientists, virologists, pharmacologists, molecular biologists, immunologists, and other researchers working in laboratories of all the advanced countries focused their research on the setting up of biotechnological tools, namely vaccines and monoclonal antibodies, as well as of rational design of drugs for therapeutic approaches. While vaccines have been quickly obtained, no satisfactory anti-Covid-19 preventive, or therapeutic approach has so far been discovered and approved. However, among the possible ways to achieve the goal of COVID-19 prevention or mitigation, there is one route, i.e., the diet, which until now has had little consideration. In fact, in the edible parts of plants supplying our food, there are a fair number of secondary metabolites mainly belonging to the large class of the flavonoids, endowed with antiviral or other health beneficial activities such as immunostimulating or anti-inflammatory action that could play a role in contributing to some extent to prevent or alleviate the viral infection and/or counteract the development of SARS induced by the novel coronavirus. In this review, a number of bioactive phytochemicals, in particular flavonoids, proven to be capable of providing some degree of protection against COVID-19, are browsed, illustrating their beneficial properties and mechanisms of action as well as their distribution in cultivated plant species which supply food for the human diet. Furthermore, room is also given to information regarding the amount in food, the resistance to cooking processes and, as a very important feature, the degree of bioavailability of these compounds. Concluding, remarks and perspectives for future studies aimed at increasing and improving knowledge and the possibility of using this natural complementary therapy to counteract COVID-19 and other viral pathologies are discussed.


Multiple-image encryption based on interference principle and phase-only mask multiplexing in Fresnel transform domain.
In this article, a multiple-image encryption method based on the optical interference principle and phase-only mask (POM) multiplexing is proposed. During the encryption process, each secret image is encoded into two analytically obtained POMs and one computer-generated random POM, in which no iterative computation is required. The analytically obtained POMs taken from different secret images are then synthesized by POM multiplexing and further encoded into two complex ciphertext images. The silhouette problem that exists in the earlier interference principle-based encryption approaches is totally resolved by the proposal. Both digital and optical means can be used for decryption. The crosstalk effect between the secret images will not appear in the decrypted results by using the proposed system. Numerical simulations have been given to verify the performance and feasibility of the proposal. We also discuss briefly the influence of information compression on the quality of decrypted images.


Impact of genetic background on allele selection in a highly mutable Candida albicans gene, PNG2.
In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8x10(-5) (confidence interval 3.3x10(-6)-9. 9x10(-5)) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term.


A Tool to Quantify the Functional Impact of Oscillopsia.
Individuals with bilateral vestibular hypofunction (BVH) often report symptoms of oscillopsia during walking. Existing assessments of oscillopsia are limited to descriptions of severity and symptom frequency, neither of which provides a description of functional limitations attributed to oscillopsia. A novel questionnaire, the Oscillopsia Functional Impact scale (OFI) was developed to describe the impact of oscillopsia on daily life activities. Questions on the OFI ask how often individuals are able to execute specific activities considered to depend on gaze stability in an effort to link functional mobility impairments to oscillopsia for individuals with vestibular loss. Subjective reports of oscillopsia and balance confidence were recorded for 21 individuals with BVH and 48 healthy controls. Spearman correlation coefficients were calculated to determine the relationship between the OFI and oscillopsia visual analog scale (OS VAS), oscillopsia severity questionnaire (OSQ), and Activities-Specific Balance Confidence scale to demonstrate face validity. Chronbach's α was calculated to determine internal validity for the items of the OFI. A one-way MANOVA was conducted with planned post hoc paired t-tests for group differences on all oscillopsia questionnaires using a corrected α = 0.0125. The OFI was highly correlated with measures of oscillopsia severity (OS VAS; r = 0.69, p < 0.001) and frequency (OSQ; r = 0.84, p < 0.001) and also with the Activities-Specific Balance Confidence scale (r = -0.84, p < 0.001). Cronbach's α for the OFI was 0.97. Individuals with BVH scored worse on all measures of oscillopsia and balance confidence compared to healthy individuals (p's < 0.001). The OFI appears to capture the construct of oscillopsia in the context of functional mobility. Combining with oscillopsia metrics that quantify severity and frequency allows for a more complete characterization of the impact of oscillopsia on an individual's daily behavior. The OFI discriminated individuals with BVH from healthy individuals.


Acyclovir use and its surveillance in a general population.
This study examined the extent and patterns of use of acyclovir in a health maintenance organization (HMO) population. The development and implementation of a system to survey acyclovir users for possible acute adverse effects is also described. Acyclovir users were members of Kaiser Permanente (KP), Northwest Region, who received one or more prescriptions for acyclovir from an automated outpatient prescription system over a two-year period (1986 and 1987). KP members with genital herpes were identified from the automated Outpatient Utilization System, which abstracts medical record data from a random sample of about two percent of KP members. Acyclovir users with hospital admissions were identified from the automated KP hospital discharge abstract system. During the two years, there were 2940 users who received a total of 6182 prescriptions for acyclovir; 47 percent used oral acyclovir and 56 percent of prescriptions were for the oral dosage form. Females received two-thirds of the prescriptions, and people 15 through 45 years of age received 80 percent of the prescriptions. The estimated incidence density of oral acyclovir usage was 2.3/1000 KP members. Most oral acyclovir prescriptions were for the treatment of genital herpes. More than 60 percent of the prescriptions appeared to be for first treatment, more than 30 percent for repeat treatment, and about 6 percent for continuing treatment. Hospitalizations of oral acyclovir users appeared to be unrelated to the use of the drug.


Intestinal damage precedes mucosal immune dysfunction in SIV infection.
HIV and pathogenic SIV infection are characterized by mucosal dysfunction including epithelial barrier damage, loss of Th17 cells, neutrophil infiltration, and microbial translocation with accompanying inflammation. However, it is unclear how and when these contributing factors occur relative to one another. In order to determine whether any of these features initiates the cycle of damage, we longitudinally evaluated the kinetics of mucosal and systemic T-cell activation, microbial translocation, and Th17 cell and neutrophil frequencies following intrarectal SIV infection of rhesus macaques. We additionally assessed the colon proteome to elucidate molecular pathways altered early after infection. We demonstrate increased T-cell activation (HLA-DR+) beginning 3-14 days post-SIV challenge, reduced peripheral zonulin 3-14 days post-SIV, and evidence of microbial translocation 14 days post-SIV. The onset of mucosal dysfunction preceded peripheral and mucosal Th17 depletion, which occurred 14-28 days post-SIV, and gut neutrophil accumulation was not observed. Proteins involved in epithelial structure were downregulated 3 days post-SIV followed by an upregulation of immune proteins 14 days post-SIV. These data demonstrate that immune perturbations such as Th17 loss and neutrophil infiltration occur after alterations to epithelial structural protein pathways, suggesting that epithelial damage occurs prior to widespread immune dysfunction.


Light emitting diodes based on carbon dots derived from food, beverage, and combustion wastes.
One important resource for material synthesis is waste. Utilization of waste as a resource for material synthesis is an environmentally responsible approach that reduces the need for virgin resources and subsequent processing. In this report a method to produce multicolored, luminescent carbon dots (CDs) and subsequent fabrication of light emitting diodes from food, beverage, and combustion wastes, is discussed. Apart from food and beverages, combustion exhaust was also utilized for CDs production. Optical characterization results suggest that CDs from waste food and beverages are more luminescent than those produced from combustion waste.


Vitamin C and cancer prevention: the epidemiologic evidence.
Epidemiologic evidence of a protective effect of vitamin C for non-hormone-dependent cancers is strong. Of the 46 such studies in which a dietary vitamin C index was calculated, 33 found statistically significant protection, with high intake conferring approximately a twofold protective effect compared with low intake. Of 29 additional studies that assessed fruit intake, 21 found significant protection. For cancers of the esophagus, larynx, oral cavity, and pancreas, evidence for a protective effect of vitamin C or some component in fruit is strong and consistent. For cancers of the stomach, rectum, breast, and cervix there is also strong evidence. Several recent lung cancer studies found significant protective effects of vitamin C or of foods that are better sources of vitamin C than of beta-carotene. It is likely that ascorbic acid, carotenoids, and other factors in fruits and vegetables act jointly. Increased consumption of fruits and vegetables in general should be encouraged.


Cranberry juice decreases disease activity in women with rheumatoid arthritis.
Studies have shown that cranberry (Vaccinium macrocarpon) has antiinflammatory and antioxidant effects; however, to our knowledge, the effects of cranberry juice consumption have not been studied in patients with rheumatoid arthritis (RA). The aim of this study was to verify the effect of cranberry juice consumption on several inflammatory biomarkers and on the disease activity of patients with RA. A prospective study was conducted with 41 women diagnosed with RA. The disease activity measured by Disease Activity Score 28 (DAS28) and anticyclic citrullinated peptide (anti-CCP) antibodies, and several inflammatory and biochemical biomarkers were analyzed. The control group (n = 18) maintained their usual diet. The cranberry group (n = 23) consumed 500 mL/d of low-calorie cranberry juice. Regarding the baseline values, the cranberry group presented a decrease in the values of DAS28 (P = 0.048) and anti-CCP (P = 0.034) after 90 d of treatment, whereas changes in inflammatory biomarkers were not found. The present study indicated that cranberry juice decreases disease activity and therefore has beneficial effects for RA patients, although larger and long-term studies are needed to definitively probe this effect and to clarify the mechanisms involved.


Prevalence of hepatitis C genotypes among patients with chronic hepatitis C in Norway. Construct Group.
Among 116 patients with biopsy-confirmed chronic hepatitis C (Riba 2 or Riba 3 positive) in a multicenter study in southern Norway on interferon, we determined hepatitis C virus genotype by restriction fragment length polymorphism (RFLP) of the 5' NCR. The RFLP method was supplemented by and compared with a serological typing method based on the detection of type-specific antibody to peptide from the NS-4 region. A total of 102/106 (96%) patient sera showed detectable type-specific antibody to NS-4 peptides and corresponded in all cases, except two, to the genotype detected by polymerase chain reaction. Combining the results from RFLP genotyping and serotyping, genotype 1 was found in 40 (35%) (27 with 1a and 10 with 1b, 3 subtypes not determined), genotype 2 in 15 (13%) (subtype 2b in 14 and 1 subtype not determined), and genotype 3 in 58 (50%) of patients. The low mean age of the patients (34 years), the low prevalence of cirrhosis (3.5%), the short duration of the disease, and a high prevalence of intravenous-drug abusers may account for the low prevalence of infection with genotype 1b (9%). The epidemiological features of hepatitis C patients are markedly different from patient groups described in southern Europe in terms of risk factors, age, and genotype distribution.


A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis.
Congenital heart disease (CHD) is the most common type of birth defects with family- and population-based studies supporting a strong hereditary component. Multifactorial inheritance is the rule although a growing number of Mendelian forms have been described including candidates that have yet to be confirmed independently. TLL1 is one such candidate that was proposed in the etiology of atrial septal defect (ASD). We describe a girl with congenitally corrected transposition of the great arteries (ccTGA) and ASD secundum whose whole-exome sequencing (WES) revealed a de novo splicing (c.1379-2A>G) variant in TLL1 as well as an inherited truncating variant in NODAL. The identification of this dual molecular diagnosis both supports the candidacy of TLL1 in ASD pathogenesis and highlights the power of WES in revealing multilocus cardiac phenotypes.


Mining and characterizing microsatellites from citrus ESTs.
Freely available computer programs were arranged in a pipeline to extract microsatellites from public citrus EST sequences, retrieved from the NCBI. In total, 3,278 bi- to hexa-type SSR-containing sequences were identified from 56,199 citrus ESTs. On an average, one SSR was found per 5.2 kb of EST sequence, with the tri-nucleotide motifs as the most abundant. Primer sequences flanking SSR motifs were successfully identified from 2,295 citrus ESTs. Among those, a subset (100 pairs) were synthesized and tested to determine polymorphism and heterozygosity between/within two genera, sweet orange (C. sinensis) and Poncirus (P. trifoliata), which are the parents of the citrus core mapping population selected for an international citrus genomics effort. Eighty-seven pairs of primers gave PCR amplification to the anticipated SSRs, of which 52 and 35 appear to be homozygous and heterozygous, respectively, in sweet orange, and 67 and 20, respectively, in Poncirus. By pairing the loci between the two intergeneric species, it was found that 40 are heterozygous in at least one species with two alleles (9), three alleles (28), or four alleles (3), and the remaining 47 are homozygous in both species with either one allele (31) or two alleles (16). These EST-derived SSRs can be a resource used for understanding of the citrus SSR distribution and frequency, and development of citrus EST-SSR genetic and physical maps. These SSR primer sequences are available upon request.


Inductive measurement of optically hyperpolarized phosphorous donor nuclei in an isotopically enriched silicon-28 crystal.
We experimentally demonstrate the first inductive readout of optically hyperpolarized phosphorus-31 donor nuclear spins in an isotopically enriched silicon-28 crystal. The concentration of phosphorus donors in the crystal was 1.5×10(15) cm(-3), 3 orders of magnitude lower than has previously been detected via direct inductive detection. The signal-to-noise ratio measured in a single free induction decay from a 1 cm(3) sample (≈10(15) spins) was 113. By transferring the sample to an X-band ESR spectrometer, we were able to obtain a lower bound for the nuclear spin polarization at 1.7 K of ∼64%. The (31)P-T2 measured with a Hahn echo sequence was 420 ms at 1.7 K, which was extended to 1.2 s with a Carr Purcell cycle. The T1 of the (31)P nuclear spins at 1.7 K is extremely long and could not be determined, as no decay was observed even on a time scale of 4.5 h. Optical excitation was performed with a 1047 nm laser, which provided above-band-gap excitation of the silicon. The buildup of the hyperpolarization at 4.2 K followed a single exponential with a characteristic time of 577 s, while the buildup at 1.7 K showed biexponential behavior with characteristic time constants of 578 and 5670 s.


Teachers with LD: Ongoing negotiations with discourses of disability.
The purpose of this study is to examine how 4 teachers with learning disabilities (LD) negotiate multiple, complex, and sometimes contradictory discourses of disabilities in constructing their own understandings of LD. We chose to study teachers with LD because of their unique access to at least 3 different sources of knowledge about LD: (a) professional discourses on disability, (b) mainstream cultural messages about LD, and (c) insights gained from their own life experience. We drew on aspects of critical discourse analysis and narrative inquiry for this investigation. Our findings indicate that participants draw on these discourses and on their teaching experience in various and complex ways to construct meaning about LD. In some instances, participants use the dominant discourses; at other times, they work to subvert these meanings. Yet, paradoxically, whether speaking with or against these meanings, their voices are inescapably engaging with authoritative discourses and cultural scripts surrounding disability.


Modelling the dynamics of intramammary E. coli infections in dairy cows: understanding mechanisms that distinguish transient from persistent infections.
The majority of intramammary infections with Escherichia coli in dairy cows result in transient infections with duration of about 10 days or less, although more persistent infections (2 months or longer) have been identified. We apply a mathematical model to explore the role of an intracellular mammary epithelial cell reservoir in the dynamics of infection. We included biological knowledge of the bovine immune response and known characteristics of the bacterial population in both transient and persistent infections. The results indicate that varying the survival duration of the intracellular reservoir reproduces the data for both transient and persistent infections. Survival in an intracellular reservoir is the most likely mechanism that ensures persistence of E. coli infections in mammary glands. Knowledge of the pathogenesis of persistent infections is essential to develop preventive and treatment programmes for these important infections in dairy cows.


Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy.
By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression. PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort. PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triple-negative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A-like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells. PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers. Clin Cancer Res; 22(9); 2271-82. ©2015 AACR.


Leukemia risk in children exposed to benzene and PM10 from vehicular traffic: a case-control study in an Italian population.
Benzene, a recognized occupational leukemogen in adults, has been hypothesized to also increase the risk of childhood leukemia. We carried out a population-based case-control study in a northern Italy community involving 83 cases with acute childhood leukemia diagnosed in the years 1998-2009 and 332 matched controls. We assessed residential exposure to benzene and to particulate matter ≤10 μm (PM10) from motorized traffic using geocoded residences and detailed emission and dispersion modeling. Exposure to benzene, and to a lesser extent to PM10, appeared to be independently associated with an excess leukemia risk. When we stratified the study population by age and by leukemia subtype, the relative risk associated with benzene exposure was higher among children aged less than 5 years, and despite small numbers this relation appeared to be considerably stronger for acute myeloid leukemia than for acute lymphoblastic leukemia. Overall, these findings suggest that exposure to low levels of benzene released from motorized traffic may increase the risk of childhood leukemia, and suggest a possible independent effect of PM10, although unmeasured confounding due to other pollutants cannot be ruled out.


Intrinsic patient factors predictive of inpatient rehabilitation facility discharge following primary total knee arthroplasty: a systematic review and meta-analysis.
Total Knee Arthroplasty (TKA) reduces pain and improves function in those suffering from severe osteoarthritis. A significant cost of TKA is post-acute care, however, current evidence suggests that discharge to an Inpatient Rehabilitation Facility (IRF) has inferior outcomes to home discharge, with no greater benefit in physical function. Only individual studies have investigated TKA patient characteristics predictive of discharge destination, therefore, the aim is to systematically review the literature and meta-analyse intrinsic patient factors predictive of IRF discharge. If predictive factors are known, then early discharge planning and intervention strategies could be implemented. Databases PubMed, CINAHL, Embase, Cochrane, and Pedro were searched up to October 2019 for all studies investigating pre-operative intrinsic patient factors predictive of IRF discharge. For assessing the methodological quality of included studies, the Quality In Prognosis Studies (QUIPS) tool was used. Statistical analysis and graphical reporting were conducted in R statistical software. To assess the effect of predictors of discharge destination, odds ratios with the corresponding 95%CI were extracted from the results of univariate and multivariable analyses. A total of 9 articles published between 2011 to 2018 with 218,151 TKA patients were included. Of the 13 intrinsic patient factors reported, 6 met the criteria for synthesised review: age, obesity, comorbidity, gender, SF-12/VR-12 survey, and smoking. Due to the heterogeneity of statistical analysis and reporting 2 variables could undergo meta-analysis, gender and smoking. Female gender increased the likelihood of IRF discharge by 78% (OR = 1.78; 95%CI = 1.43-2.20; I2 = 33.3%), however, the relationship between smoking status and discharge destination was less certain (OR = 0.80; 95%CI = 0.42-1.50; I2 = 68.5%). In this systematic literature review and meta-analysis female gender was shown to be predictive of IRF discharge after total knee arthroplasty. There was also a trend for those of older age and increased comorbidity, as measured by the Charlson Comorbidity Index, or the severely obese to have an increased likelihood of IRF discharge. The marked heterogeneity of statistical methods and reporting in existing literature made pooled analysis challenging for intrinsic patient factors predictive of IRF discharge after TKA. Further, high quality studies of prospective design on predictive factors are warranted, to enable early discharge planning and optimise resource allocation on post-acute care following TKA. This review was registered with PROSPERO ( CRD42019134422 ).


Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity.
Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but mechanisms for its activation and regulation remain unknown. We found here that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1; this resulted in activation of IRAK1 and facilitated its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-deficient cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant activation of IRAK1 and type I interferons in various immune diseases, controlling IRAK1 activation via inhibition of Pin1 may represent a useful therapeutic approach.


Harnessing 13C-labeled myo-inositol to interrogate inositol phosphate messengers by NMR.
Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are an important group of metabolites and mediate a wide range of processes in eukaryotic cells. To elucidate the functions of these molecules, robust techniques for the characterization of inositol phosphate metabolism are required, both at the biochemical and the cellular level. Here, a new tool-set is reported, which employs uniformly 13C-labeled compounds ([13C6]myo-inositol, [13C6]InsP5, [13C6]InsP6, and [13C6]5PP-InsP5), in combination with commonly accessible NMR technology. This approach permitted the detection and quantification of InsPs and PP-InsPs within complex mixtures and at physiological concentrations. Specifically, the enzymatic activity of IP6K1 could be monitored in vitro in real time. Metabolic labeling of mammalian cells with [13C6]myo-inositol enabled the analysis of cellular pools of InsPs and PP-InsPs, and uncovered high concentrations of 5PP-InsP5 in HCT116 cells, especially in response to genetic and pharmacological perturbation. The reported method greatly facilitates the analysis of this otherwise spectroscopically silent group of molecules, and holds great promise to comprehensively analyze inositol-based signaling molecules under normal and pathological conditions.


[Deoxycholic acid-induced signal transduction in HT-29 cells: role of NF-kappa B and interleukin-8].
Deoxycholic acid (DCA) has been appeared to be an endogenous colon tumor promoter. In this study, we investigated whether DCA induces nuclear factor-kappa B (NF-kappa B) activation and IL-8 expression, and tauroursodeoxycholic acid (TUDC) inhibits this signaling in HT-29 cells. After DCA treatments, time courses of NF-kappa B binding activity were determined by electrophoretic mobility shift assay (EMSA). Also, we performed Western blotting of I kappa B alpha to confirm NF-kappa B activation. Time and concentration courses of DCA-induced secretion of IL-8 were measured with ELISA in supernatants of cultured media from the cells. To evaluate the role of NF-kappa B, IL-8 levels were assessed after pretreatment with using phosphorothioate-modified anti-sense oligonucleotides (ODN). Moreover, DCA-induced secretions of IL-8 were measured after pretreatment with TUDC. DCA dose-dependently induced prominent NF-kappa B binding complexes from 30 min to 8 hr and degradation of I kappa B alpha. The secretions of IL-8 were increased with DCA (50-200 micro M) treatment in a time and dose-dependent manner. Pre-incubation of the cells with TUDC (0.1-10 micro M) for 2 hours caused significant decreases in DCA induced IL-8 secretion. However, transient transfection using p50 or p65 AS-ODN showed no effect on IL-8 secretion. DCA may play as a colonic tumor promoter through anti-apoptotic effect of NF-kappa B activation and IL-8 expression, and DCA-induced NF-kappa B independent IL-8 expression is inhibited by TUDC.


Temperature-induced activation of freshwater Cyanophage AS-1 prophage.
Synechococcus sp. IU 625 is one of the freshwater cyanobacteria responsible for harmful algal blooms (HAB). Cyanophages can serve as natural control agents and may be responsible for algal bloom prevention and disappearance. Cyanophage AS-1, which infects Synechococcus sp. IU 625 (Anacystis nidulans) and Synechococcus cedrorum, plays an important role in the environment, significantly altering the numbers of its hosts. Since seasonal (temperature-dependent) lytic induction of cyanobacterial prophage has been proposed to affect seawater algal blooms, we investigated if the AS-1 lytic cycle could be induced by a shift to high temperature. Our hypothesis was confirmed, as more phages were released at 35°C than at 24°C, with maximal induction observed with a shift from 24 to 35°C. Furthermore, transmission electron microscopy (TEM) images provide direct evidence of lysogenic to lytic conversion with temperature shift. Thus, temperature is an important inducer for AS-1 conversion from lysogenic to lytic cycle and could have applications in terms of modulating cyanobacterial populations in freshwater aquatic environments. The study gives insight into the effect of climate change on the interaction between cyanophage and cyanobacteria in freshwater ecosystems.


Different Conformations of 2'-Deoxycytidine in the Gas and Solid Phases: Competition between Intra- and Intermolecular Hydrogen Bonds.
Computational results have been reported for 2'-deoxycytidine (dC), its gas phase isomers, tautomers, and their conformers, as well as for the crystalline phase. In addition to the neutral gas phase molecules, we have also considered associated radical anions and cations. The structural calculations were performed at the density functional and MP2 levels of theory. Vertical electron ionization energies and excess electron binding energies were determined using electron propagator theory. The α-anomer proved to be more stable by a fraction of kcal/mol than the biologically relevant canonical β-anomer. The conformational space of canonical dC has been systematically probed. dC in the crystalline phase or DNA structures favors canonical anti conformations. These structures were used in past computational studies to model gas phase characteristics of dC. Our findings indicate, however, that the gas phase dC favors syn conformations. It has repercussions for earlier interpretations of gas phase experimental results based on these computational results. The thermodynamic dominance of syn conformations results from the formation of an intramolecular O5'-H13···O2 hydrogen bond. The IR spectra of the most stable syn and anti canonical conformers differ markedly in the region of frequencies corresponding to NH/OH stretching modes. The MP2 value of deprotonation enthalpy of dC of 1411.7 kJ/mol is in very good agreement with the experimental value of 1409 ± 2.5 kJ/mol. The most stable valence anions are characterized by electron vertical detachment energies (VDE) in the 0.8-1.0 eV range, in good agreement with the experimental VDE of 0.87 eV. The barrier for the glycosidic bond cleavage is significant in the neutral canonical dC, 40.0 kcal/mol, and it is reduced to 22 and 16 kcal/mol for the anionic and cationic radicals of dC, respectively. The cleavage reaction is exothermic by 4 kcal/mol for dC- and endothermic by 7 and 9 kcal/mol for dC+ and dC, respectively. We decomposed the crystal cohesive energy into repulsive one-body terms associated with the syn-anti conformational changes, and the attractive intermolecular interaction term. We exposed that the syn-anti conformational changes are very favorable for intermolecular interactions; in particular they make the imino-amino side of the cytosine residue accessible to intermolecular interactions.


The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.
Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.


Isoenzyme differentiation of Aedes aegypti populations in French Guiana.
Population genetics of peri-domestic Aedes aegypti (Diptera: Culicidae), vector of dengue and yellow fever, were investigated by gel electrophoresis of 10 enzyme loci in 14 samples of mosquito larvae collected in 1997-1998 from localities separated by distances of 3-275 km in French Guiana. Genetic differentiation between geographical populations was generally high (mean FST = +0.111, P < 10(-5)) even among seven sites <30 km apart (FST = +0.137, P < 0.05), but not positively correlated with distance. Thus, Ae. aegypti comprises a mosaic of genetically differentiated populations in French Guiana. This may be attributed to reinvasion from diverse origins through repeated founder events after this vector species was eliminated during the 1940s to 1960s.


Systemic sclerosis and occupational risk factors: role of solvents and cleaning products.
To analyze occupational and non-occupational exposure factors suspected of being associated with scleroderma (SSc), with a view to inculpating or excluding certain potentially toxic substances (e.g., solvents), thereby contributing to the recognition of such toxins in the field of occupational health. The study comprised 10 men and 83 women diagnosed with SSc between 1995 and 1999 (American College of Rheumatology criteria) and early SSc, and 206 age and sex matched controls. The SSc registry is all-inclusive in the French administrative departments of Isere and Savoie so controls were randomly selected from the general population (using telephone directories) in these departments to ensure full representation. Exposure factors were analyzed for each subject by a personal questionnaire, and an individual evaluation was carried out by an industrial expert. Data were analyzed by conditional logistical regression adjusting for educational level. Construction workers were at significantly higher risk of contracting SSc; odds ratio (OR) = 4.01 (95% confidence interval 1.14-14.09). Analysis by industrial experts identified exposure to certain toxic substances regularly used by these same workers as risk factors for SSc: cleaning products: OR = 1.66 (0.90-3.08) (both sexes) and OR = 1.71 (0.92-3.20) (women only); solvents: OR = 3.23 (1.58-6.63) (both sexes) and OR = 2.80 (1.28-6.11) (women only); synthetic adhesives: OR 25.36 (1.36-472.28) (on 3 exposed cases). Exposure to either cleaning products or solvents emerged as a risk factor for SSc. Exposure factors should be characterized and results of all studies compared to implement appropriate preventive measures in relevant workplaces.


Elliptic-symmetry vector optical fields.
We present in principle and demonstrate experimentally a new kind of vector fields: elliptic-symmetry vector optical fields. This is a significant development in vector fields, as this breaks the cylindrical symmetry and enriches the family of vector fields. Due to the presence of an additional degrees of freedom, which is the interval between the foci in the elliptic coordinate system, the elliptic-symmetry vector fields are more flexible than the cylindrical vector fields for controlling the spatial structure of polarization and for engineering the focusing fields. The elliptic-symmetry vector fields can find many specific applications from optical trapping to optical machining and so on.


Self-administration of exercise and dietary supplements in deployed British military personnel during Operation TELIC 13.
Recent operational experience has led to the identification of several potentially serious adverse events related to the use of dietary and exercise supplements among British Army personnel. This study aimed to establish the point prevalence of dietary and exercise supplement usage in British soldiers on Op TELIC during January 2009. A cross-sectional questionnaire-based study of British military personnel located at the Contingency Operating Base (COB), in Basra, was performed during the sixth week of Op TELIC 13. From 1544 questionnaires (target population) issued, a total of 1017 (65.9%) completed questionnaires were evaluated. The mean population age was 29.5 years (range 18-58) of which 87.4% were male. 417/1017 persons (41.0%) admitted to a history of supplement use of which 32.0% were current users and 9.4% were previous users. Of these current users, 66.0% started taking them on their current deployment. The most commonly taken supplements were whey protein (18.8%), amino acids (17.9%), and creatine (13.2%). There were 14 persons (1.4%) who admitted to current use of anabolic steroids. The most-frequently given reasons for taking supplements were either to 'increase muscle bulk' (40.4%) or to aid training and recovery (20.8%). This is the first study to investigate the use of exogenous nutritional supplements within the British Military and has identified their widespread use during operational deployment. The use of anabolic steroids is particularly worrying, given both their illegality and their well-recognised and deleterious health effects. There is a need for greater awareness and education regarding potential benefits and dangers of supplement use in order to maximise any potential benefits and minimise clinical risk.


New perspectives in ocean acidification research: editor's introduction to the special feature on ocean acidification.
Ocean acidification, caused by the uptake of additional carbon dioxide (CO2) from the atmosphere, will have far-reaching impacts on marine ecosystems (Gattuso & Hansson 2011 Ocean acidification Oxford University Press). The predicted changes in ocean chemistry will affect whole biological communities and will occur within the context of global warming and other anthropogenic stressors; yet much of the biological research conducted to date has tested the short-term responses of single species to ocean acidification conditions alone. While an important starting point, these studies may have limited predictive power because they do not account for possible interactive effects of multiple climate change drivers or for ecological interactions with other species. Furthermore, few studies have considered variation in responses among populations or the evolutionary potential within populations. Therefore, our knowledge about the potential for marine organisms to adapt to ocean acidification is extremely limited. In 2015, two of the pioneers in the field, Ulf Riebesell and Jean-Pierre Gattuso, noted that to move forward as a field of study, future research needed to address critical knowledge gaps in three major areas: (i) multiple environmental drivers, (ii) ecological interactions and (iii) acclimation and adaptation (Riebesell and Gattuso 2015 Nat. Clim. Change5, 12-14 (doi:10.1038/nclimate2456)). In May 2016, more than 350 researchers, students and stakeholders met at the 4th International Symposium on the Ocean in a High-CO2 World in Hobart, Tasmania, to discuss the latest advances in understanding ocean acidification and its biological consequences. Many of the papers presented at the symposium reflected this shift in focus from short-term, single species and single stressor experiments towards multi-stressor and multispecies experiments that address knowledge gaps about the ecological impacts of ocean acidification on marine communities. The nine papers in this Special Feature are from authors who attended the symposium and address cutting-edge questions and emerging topics in ocean acidification research, across the taxonomic spectrum from plankton to top predators. They cover the three streams of research identified as crucial to understanding the biological impacts of ocean acidification: (i) the relationship with other environmental drivers, (ii) the effects on ecological process and species interactions, and (iii) the role that individual variation, phenotypic plasticity and adaptation will have in shaping the impacts of ocean acidification and warming on marine ecosystems.


High density lipoproteins-based therapies for cardiovascular disease.
Atherosclerosis is the leading cause of death in developed countries. High density lipoproteins (HDL) cholesterol level correlates inversely with the risk of cardiovascular diseases. Thus, HDL has obtained lots of interest for drug development. In this review, we summarized the mechanisms for the antiatherogenic function of HDL, current HDL-based drugs in clinical use and the future direction for HDL-based therapy development.


Flower vs. leaf feeding by Pieris brassicae: glucosinolate-rich flower tissues are preferred and sustain higher growth rate.
Interactions between butterflies and caterpillars in the genus Pieris and plants in the family Brassicaceae are among the best explored in the field of insect-plant biology. However, we report here for the first time that Pieris brassicae, commonly assumed to be a typical folivore, actually prefers to feed on flowers of three Brassica nigra genotypes rather than on their leaves. First- and second-instar caterpillars were observed to feed primarily on leaves, whereas late second and early third instars migrated via the small leaves of the flower branches to the flower buds and flowers. Once flower feeding began, no further leaf feeding was observed. We investigated growth rates of caterpillars having access exclusively to either leaves of flowering plants or flowers. In addition, we analyzed glucosinolate concentrations in leaves and flowers. Late-second- and early-third-instar P. brassicae caterpillars moved upward into the inflorescences of B. nigra and fed on buds and flowers until the end of the final (fifth) instar, after which they entered into the wandering stage, leaving the plant in search of a pupation site. Flower feeding sustained a significantly higher growth rate than leaf feeding. Flowers contained levels of glucosinolates up to five times higher than those of leaves. Five glucosinolates were identified: the aliphatic sinigrin, the aromatic phenylethylglucosinolate, and three indole glucosinolates: glucobrassicin, 4-methoxyglucobrassicin, and 4-hydroxyglucobrassicin. Tissue type and genotype were the most important factors affecting levels of identified glucosinolates. Sinigrin was by far the most abundant compound in all three genotypes. Sinigrin, 4-hydroxyglucobrassicin, and phenylethylglucosinolate were present at significantly higher levels in flowers than in leaves. In response to caterpillar feeding, sinigrin levels in both leaves and flowers were significantly higher than in undamaged plants, whereas 4-hydroxyglucobrassicin leaf levels were lower. Our results show that feeding on flower tissues, containing higher concentrations of glucosinolates, provides P. brassicae with a nutritional benefit in terms of higher growth rate. This preference appears to be in contrast to published negative effects of volatile glucosinolate breakdown products on the closely related Pieris rapae.


A valuable approach to the use of electronic medical data in primary care research: Panning for gold.
Electronic medical data (EMD) from electronic health records of general practice computer systems have enormous research potential, yet many variables are unreliable. The aim of this study was to compare selected data variables from general practice EMD with a reliable, representative national dataset (Bettering the Evaluation and Care of Health (BEACH)) in order to validate their use for primary care research. EMD variables were compared with encounter data from the nationally representative BEACH program using χ2 tests and robust 95% confidence intervals to test their validity (measure what they reportedly measure). The variables focused on for this study were patient age, sex, smoking status and medications prescribed at the visit. The EMD sample from six general practices in the Illawarra region of New South Wales, Australia, yielded data on 196,515 patient encounters. Details of 90,553 encounters were recorded in the 2013 BEACH dataset from 924 general practitioners. No significant differences in patient age ( p = 0.36) or sex ( p = 0.39) were found. EMD had a lower rate of current smokers and higher average scripts per visit, but similar prescribing distribution patterns. Validating EMD variables offers avenues for improving primary care delivery and measuring outcomes of care to inform clinical practice and health policy.


The First Report of Leaf Spots in Aloe vera Caused by Nigrospora oryzae in China.
Aloe vera L. var Chinese (Haw) Berg is a popular ornamental plant cultivated worldwide, whose extracts are used in cosmetics and medicine. Aloe plants are commonly affected by leaf spot disease caused by Alternaria alternata in Pakistan, India, and the United States (1). An outbreak of Alternaria leaf spot recently threatened aloe gel production and the value of ornamental commerce in Louisiana (1). During the summer of 2011, leaf spot symptoms were observed on A. vera plants growing in several greenhouses and ornamental gardens in Wuhan, Hubei Province, China. In two of the greenhouses, disease incidence reached 50 to 60%. The initial symptoms included chlorotic and brown spots that expanded to 2 to 4 mm in diameter and became darker with age. Lesions also developed on the tips of 30 to 50% of the leaves per plant. In severe infections, the lesions coalesced causing the entire leaf to become blighted and die. In September of 2012 and February of 2013, 10 symptomatic A. vera leaves were collected randomly from two greenhouses and gardens in Wuhan. A fungus was consistently recovered from approximately 80% of the tissue samples using conventional sterile protocols, and cultured on potato dextrose agar (PDA). The colonies were initially white, becoming grey to black, wool-like, and growing aerial mycelium covering the entire petri dish (9 cm in diameter) plate within 5 days when maintained in the dark at 25°C. The conidia were brown or black, spherical to subspherical, single celled (9 to 13 μm long × 11 to 15 μm wide), borne on hyaline vesicles at the tip of conidiophores. The conidiophores were short and rarely branched. These colonies were identified as Nigrospora oryzae based on the described morphological characteristics of N. oryzae (2). Genomic DNA was extracted from a representative isolate, LH-1, and the internal transcribed spacer region was amplified using primer pair ITS1/ITS4 (3). A 553-bp amplicon was obtained and sequenced. The resulting nucleotide sequence (GenBank Accession No. KC519728) had a high similarity of 99% to that of strain AHC-1 of N. oryzae (JQ864579). Pathogenicity tests for strain LH-1 were conducted in triplicate by placing agar pieces (5 mm in diameter) containing 5-day-old cultures on A. vera leaves. Four discs were placed on each punctured surface of each leaf. Noncolonized PDA agar pieces were inoculated as controls. Leaves were placed in moist chambers at 25°C with a 12-h photoperiod. After 3 days, the inoculated leaves showed symptoms similar to those observed in the greenhouses. N. oryzae was reisolated from these spots on the inoculated leaves. No visible symptoms developed on the control leaves. The pathogenicity tests were performed twice with the same results. Based on the results, N. oryzae was determined as a pathogen responsible for the leaf spots disease on A. vera. N. oryzae has been described as a leaf pathogen on fig (Ficus religiosa), cotton (Gossypium hirsutum) and Kentucky bluegrass (Poa pratensis) (4), and to our knowledge, this is the first report of N. oryae causing leaf spot disease on A. vera worldwide. References: (1) W. L. da Silva and R. Singh. Plant Dis. 86:1379, 2012. (2) M. B. Ellis. Dematiaceous Hyphomycetes, CAB, Kew, Surrey, England, 1971. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990. (4) L. X. Zhang et al. Plant Dis. 96:1379, 2012.


Engineering Recombinant Reoviruses To Display gp41 Membrane-Proximal External-Region Epitopes from HIV-1.
The gp41 membrane-proximal external region (MPER) is a target for broadly neutralizing antibody responses against human immunodeficiency virus type 1 (HIV-1). However, replication-defective virus vaccines currently under evaluation in clinical trials do not efficiently elicit MPER-specific antibodies. Structural modeling suggests that the MPER forms an α-helical coiled coil that is required for function and immunogenicity. To maintain the native MPER conformation, we used reverse genetics to engineer replication-competent reovirus vectors that displayed MPER sequences in the α-helical coiled-coil tail domain of viral attachment protein σ1. Sequences in reovirus strain type 1 Lang (T1L) σ1 were exchanged with sequences encoding HIV-1 strain Ba-L MPER epitope 2F5 or the entire MPER. Individual 2F5 or MPER substitutions were introduced at virion-proximal or virion-distal sites in the σ1 tail. Recombinant reoviruses containing heterologous HIV-1 sequences were viable and produced progeny yields comparable to those with wild-type virus. HIV-1 sequences were retained following 10 serial passages in cell culture, indicating that the substitutions were genetically stable. Recombinant viruses engineered to display the 2F5 epitope or full-length MPER in σ1 were recognized by purified 2F5 antibody. Inoculation of mice with 2F5-containing vectors or rabbits with 2F5- or MPER-containing vectors elicited anti-reovirus antibodies, but HIV-1-specific antibodies were not detected. Together, these findings indicate that heterologous sequences that form α-helices can functionally replace native sequences in the α-helical tail domain of reovirus attachment protein σ1. However, although these vectors retain native antigenicity, they were not immunogenic, illustrating the difficulty of experimentally inducing immune responses to this essential region of HIV-1. IMPORTANCE Vaccines to protect against HIV-1, the causative agent of AIDS, are not approved for use. Antibodies that neutralize genetically diverse strains of HIV-1 bind to discrete regions of the envelope glycoproteins, including the gp41 MPER. We engineered recombinant reoviruses that displayed MPER epitopes in attachment protein σ1 (REO-MPER vectors). The REO-MPER vectors replicated with wild-type efficiency, were genetically stable, and retained native antigenicity. However, we did not detect HIV-1-specific immune responses following inoculation of the REO-MPER vectors into small animals. This work provides proof of principle for engineering reovirus to express antigenic epitopes and illustrates the difficulty in eliciting MPER-specific immune responses.


X linked mental retardation and infantile spasms in a family: new clinical data and linkage to Xp11.4-Xp22.11.
In order to describe the neurological abnormalities and to identify the gene localisation, we re-evaluated a previously reported family with X linked mental retardation (XLMR). Reliable data were obtained for six of the seven affected males, of whom two had had infantile spasms. Profound MR (IQ<20) was found in one and mild MR (IQ 50-70) in five males. No dysmorphic features, except for macrocephaly in one male, were found. Neurological abnormalities included varying degrees of spinocerebellar involvement. Neuroimaging studies showed abnormalities, such as cerebellar atrophy or corpus callosum hypoplasia or both, in three of the six males. Several affected and unaffected subjects suffered from hyperhidrosis, which appeared to segregate independently as an autosomal dominant trait. Genetic linkage analysis localised the XLMR disease gene to Xp11.4-Xp22.11 with a maximum multipoint lod score of 3.57, overlapping the candidate region recently found in two Belgian XLMR-infantile spasm families. Compared to the Belgian patients, the majority of the affected males in this report had a considerably milder phenotype.


The financial burden from non-communicable diseases in low- and middle-income countries: a literature review.
Non-communicable diseases (NCDs) were previously considered to only affect high-income countries. However, they now account for a very large burden in terms of both mortality and morbidity in low- and middle-income countries (LMICs), although little is known about the impact these diseases have on households in these countries. In this paper, we present a literature review on the costs imposed by NCDs on households in LMICs. We examine both the costs of obtaining medical care and the costs associated with being unable to work, while discussing the methodological issues of particular studies. The results suggest that NCDs pose a heavy financial burden on many affected households; poor households are the most financially affected when they seek care. Medicines are usually the largest component of costs and the use of originator brand medicines leads to higher than necessary expenses. In particular, in the treatment of diabetes, insulin--when required--represents an important source of spending for patients and their families. These financial costs deter many people suffering from NCDs from seeking the care they need. The limited health insurance coverage for NCDs is reflected in the low proportions of patients claiming reimbursement and the low reimbursement rates in existing insurance schemes. The costs associated with lost income-earning opportunities are also significant for many households. Therefore, NCDs impose a substantial financial burden on many households, including the poor in low-income countries. The financial costs of obtaining care also impose insurmountable barriers to access for some people, which illustrates the urgency of improving financial risk protection in health in LMIC settings and ensuring that NCDs are taken into account in these systems. In this paper, we identify areas where further research is needed to have a better view of the costs incurred by households because of NCDs; namely, the extension of the geographical scope, the inclusion of certain diseases hitherto little studied, the introduction of a time dimension, and more comparisons with acute illnesses.


Deregulated semantic cognition follows prefrontal and temporo-parietal damage: evidence from the impact of task constraint on nonverbal object use.
Semantic cognition, which encompasses all conceptually based behavior, is dependent on the successful interaction of two key components: conceptual representations and regulatory control. Qualitatively distinct disorders of semantic knowledge follow damage to the different parts of this system. Previous studies have shown that patients with multimodal semantic impairment following CVA--a condition referred to as semantic aphasia (SA)--perform poorly on a range of conceptual tasks due to a failure of executive control following prefrontal and/or temporo-parietal infarction [Jefferies, E., & Lambon Ralph, M. A. Semantic impairment in stroke aphasia versus semantic dementia: A case-series comparison. Brain, 129, 2132-2147, 2006]. Although a deficit of core semantic control would be expected to impair all modalities in parallel, most research exploring this condition has focused on tasks in the verbal domain. In a novel exploration of semantic control in the nonverbal domain, therefore, we assessed eight patients with SA on two experiments that examined object use knowledge under different levels of task constraint. Patients exhibited three key characteristics of semantic deregulation: (a) difficulty using conceptual knowledge flexibly to support the noncanonical uses of everyday objects; (b) poor inhibition of semantically related distractor items; and (c) improved object use with the provision of more tightly constraining task conditions following verbal and pictorial cues. Our findings are consistent with the notion that a neural network incorporating the left inferior prefrontal and temporo-parietal areas (damaged in SA) underpins regulation of semantic activation across both verbal and nonverbal modalities.


Antibiotics and probiotics in inflammatory bowel disease: why, when, and how.
To summarize recent evidence on the role of intestinal bacteria in inflammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined. The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohn's disease has not been confirmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohn's disease, but their role in the pathogenesis of this condition remains to be defined. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohn's disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difficile infection. Recent literature provides increasing support for the use of antibiotics in Crohn's disease, although the side effects limit their long-term use. The efficacy of antibiotics in ulcerative colitis is not confirmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inflammatory bowel disease.


Enhanced and suppressed infrared transmission through germanium subwavelength arrays.
We have studied the zero-order transmission of periodic germanium (Ge) subwavelength arrays in an infrared range by using finite-difference time-domain simulations. A special wavelength-selective peak in a triangular hole array of Ge film is observed with an enhanced transmission accompanied by a drastic suppression nearby, which cannot be found in a one-dimensional Ge subwavelength array and is different from the extraordinary transmission related to surface plasmons in a metal film. The electromagnetic field is found to be concentrated on both surfaces of the Ge film at this peak. The unique transmission is verified through measurements on fabricated samples and is interpreted using the photonic band structure.


Structure and synthesis of influenza virus complementary RNAs.
Two classes of genome transcript are involved in the replication of influenza viruses, both of which contain molecules complementary to all eight genome RNAs. One of these classes, which comprises the viral mRNAs, consists of transcripts that have additional 5' terminal non-viral sequences including "cap" structures and 3' terminal polyadenylate sequences but which lack sequences corresponding to nucleotides 1-16 at the 5' termini of the virus RNAs. The members of the other class are complete genome transcripts with no additional sequences and these are thought to be the templates for genome replication. The syntheses of the two classes of molecules have a number of distinctive features which together with their structural properties indicate that they are synthesized by different mechanisms.


Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis.
Nuclear factor kappa B (NF-kappa B) activation has been observed in human atherosclerotic plaques and is enhanced in unstable coronary plaques, but whether such activation has a protective or pathophysiological role remains to be determined. We addressed this question by developing a short-term culture system of cells isolated from human atherosclerotic tissue, allowing efficient gene transfer to directly investigate signaling pathways in human atherosclerosis. We found that NF-kappa B is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-kappa B activation can be blocked by overexpression of I kappa B alpha or dominant-negative I kappa B kinase (IKK)-2 but not dominant-negative IKK-1 or NF-kappa B-inducing kinase, resulting in selective inhibition of inflammatory cytokines (tumor necrosis factor alpha, IL-6, and IL-8), tissue factor, and matrix metalloproteinases without affecting the antiinflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-kappa B activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective up-regulation of major proinflammatory and prothrombotic mediators of the disease.


Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment.
Nausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are more severe and the most severe form of NVP - hyperemesis gravidarum (HG) - affects 0.3-1.0% of pregnant women. There is no widely accepted point at which NVP becomes HG. This study aimed to determine the relative clinical effectiveness and cost-effectiveness of treatments for NVP and HG. MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, PsycINFO, Commonwealth Agricultural Bureaux (CAB) Abstracts, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, British Nursing Index, Science Citation Index, Social Sciences Citation Index, Scopus, Conference Proceedings Index, NHS Economic Evaluation Database, Health Economic Evaluations Database, China National Knowledge Infrastructure, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from inception to September 2014. References from studies and literature reviews identified were also examined. Obstetric Medicine was hand-searched, as were websites of relevant organisations. Costs came from NHS sources. A systematic review of randomised and non-randomised controlled trials (RCTs) for effectiveness, and population-based case series for adverse events and fetal outcomes. Treatments: vitamins B6 and B12, ginger, acupressure/acupuncture, hypnotherapy, antiemetics, dopamine antagonists, 5-hydroxytryptamine receptor antagonists, intravenous (i.v.) fluids, corticosteroids, enteral and parenteral feeding or other novel treatment. Two reviewers extracted data and quality assessed studies. Results were narratively synthesised; planned meta-analysis was not possible due to heterogeneity and incomplete reporting. A simple economic evaluation considered the implied values of treatments. Seventy-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder (n = 20) it was unclear. The non-randomised studies (n = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo (n = 12); steroid versus usual treatment (n = 7); ginger versus placebo (n = 6); ginger versus vitamin B6 (n = 6); and vitamin B6 versus placebo (n = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin® [Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices. The main limitations were the quantity and quality of the data available. There was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and larger trials of the main therapies considered within the UK NHS are needed. This study is registered as PROSPERO CRD42013006642. The National Institute for Health Research Health Technology Assessment programme.


Cell aging in relation to stress arousal and cardiovascular disease risk factors.
We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.


Arrhythmogenesis in the heart: Multiscale modeling of the effects of defibrillation shocks and the role of electrophysiological heterogeneity.
The mechanisms of initiation of ventricular arrhythmias as well as those behind the complex spatiotemporal wave dynamics and its filament organization during ventricular fibrillation (VF) are the topic of intense research and debate. Mechanistic inquiry into the various mechanisms that lead to arrhythmia initiation and VF maintenance is hampered by the inability of current experimental techniques to resolve, with sufficient accuracy, electrical behavior confined to the depth of the ventricles. The objective of this article is to demonstrate that realistic 3D simulations of electrical activity in the heart are capable of bringing a new level of understanding of the mechanisms that underlie arrhythmia initiation and subsequent organization. The article does this by presenting the results of two multiscale simulation studies of ventricular electrical behavior. The first study aims to uncover the mechanisms responsible for rendering the ventricles vulnerable to electric shocks during a specific interval of time, the vulnerable window. The second study focuses on elucidating the role of electrophysiological heterogeneity, and specifically, differences in action potential duration in various ventricular structures, in VF organization. Both studies share common multiscale modeling approaches and analysis, including characterization of scroll-wave filament dynamics.


Avian visual behavior and the organization of the telencephalon.
Birds have excellent visual abilities that are comparable or superior to those of primates, but how the bird brain solves complex visual problems is poorly understood. More specifically, we lack knowledge about how such superb abilities are used in nature and how the brain, especially the telencephalon, is organized to process visual information. Here we review the results of several studies that examine the organization of the avian telencephalon and the relevance of visual abilities to avian social and reproductive behavior. Video playback and photographic stimuli show that birds can detect and evaluate subtle differences in local facial features of potential mates in a fashion similar to that of primates. These techniques have also revealed that birds do not attend well to global configural changes in the face, suggesting a fundamental difference between birds and primates in face perception. The telencephalon plays a major role in the visual and visuo-cognitive abilities of birds and primates, and anatomical data suggest that these animals may share similar organizational characteristics in the visual telencephalon. As is true in the primate cerebral cortex, different visual features are processed separately in the avian telencephalon where separate channels are organized in the anterior-posterior axis roughly parallel to the major laminae. Furthermore, the efferent projections from the primary visual telencephalon form an extensive column-like continuum involving the dorsolateral pallium and the lateral basal ganglia. Such a column-like organization may exist not only for vision, but for other sensory modalities and even for a continuum that links sensory and limbic areas of the avian brain. Behavioral and neural studies must be integrated in order to understand how birds have developed their amazing visual systems through 150 million years of evolution.


Is time-slice analysis superior to total hospital length of stay in demonstrating the effectiveness of a month-long intensive effort on a medicine service?
To control the upward spiral of healthcare costs, hospitals seek to implement efficiency interventions whose benefits are frequently assessed by reductions in average inpatient length of stay (LOS). However, average hospital LOS is a crude metric when trying to assess the utility of an intervention focussed on a particular service or over a specific time window. It cannot isolate the time or place of the intervention from the full duration of a patient's hospital visit, which may include more than 1 hospital service or extend beyond the intervention's time window. At Montefiore Medical Center, a new analytic method was used to describe a month-long effort to improve care efficiency in a hospital teaching service. Using an extension of the Cox proportional hazard model (S-plus), we were able to analyze the contribution of only those patient-days that took place during the time window of interest on the service of interest, eliminating the contamination of the "non intervention days." Having built the appropriate model, we were then able to graph the behavior of the groups with and without the intervention and calculate the model's expected average LOS, controlling for the appropriate variables. By comparing this method with a conventional average LOS analysis, we demonstrate the superiority of using this "time slice" method over the conventional analysis of LOS.