bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectories of language delay from age 3 to 5: persistence, recovery and late onset
Authors: Zambrana Imac Maria , Pons Francisco , Eadie Patricia , Ystrom Eivind
Published: December 2013

Background

Knowledge is scarce on what contributes to whether children with early language delay (LD) show persistent, recovering or sometimes late‐onset LD without a prior history of early LD in subsequent preschool years.

Aims

To explore whether an integrative model of vital risk factors, including poor early communication skills, family history of language‐related difficulties and male gender, predicts the development of persistent, recovering or late‐onset LD trajectories from 3 to 5 years quantitatively and qualitatively differently.

Methods & Procedures

LD was assessed by maternal reports on the Ages and Stages Questionnaire at 3 and 5 years for 10 587 children in The Norwegian Mother and Child Cohort Study. Children were classified across time as having no, late onset, transient or persistent LD. Multinomial logistic regression analyses included the integrative model of vital risk factors and covariates.

Outcome & Results

Across time, 3%, 5% and 6.5% of the children displayed persistent, transient and late‐onset LD, respectively. The odds for persistent LD were doubled for boys and children with low language comprehension at 1.5 years; and tripled by late‐talking familial risk. These same odds decreased for transient LD, and even further for late‐onset LD. Familial risk for writing and reading difficulties especially increased the odds for late‐onset and persistent LD, while familial risk of unintelligible speech increased the odds for transient LD. Although girls had on average far better language comprehension than boys, low language comprehension was a stronger risk factor for persistent LD in girls.

Conclusions & Implications

Preschool LD trajectories were uniquely predicted from the integrative risk model of poor early communicative skills, family history and male gender. This might benefit identification of different LD trajectories by supporting broader severe vulnerability for persistent LD, milder vulnerability for transient LD, and possibly a specific risk for reading and learning difficulties for children with late‐onset LD.
Cloning of a putative extracellular Cu/Zn superoxide dismutase and functional differences of superoxide dismutases in invasive and indigenous whiteflies
Authors: Gao Xian‐Long , Li Jun‐Min , Xu Hong‐Xing , Yan Gen‐Hong , Jiu Min , Liu Shu‐Sheng , Wang Xiao‐Wei
Published: December 2013

Superoxide dismutases (SODs) are a group of important antioxidant defense enzymes. In this study, a putative extracellular Cu/Zn superoxide dismutase (ecCuZnSOD) complementary DNA was cloned and characterized from the whitefly, Bemisia tabaci. Quantitative polymerase chain reaction analysis showed that the expression level of Bt‐ecCuZnSOD was more than 10‐fold higher in the invasive Middle East Asia Minor 1 (MEAM1) than in the native Asia II 3 species of the B. tabaci species complex. After exposure to low temperature (4 °C), the expression of Bt‐ecCuZnSOD gene was significantly up‐regulated in MEAM1 but not in Asia II 3. Furthermore, the expression level of B. tabaci intracellular CuZnSOD (Bt‐icCuZnSOD), Bt‐ecCuZnSOD and mitochondrial MnSOD (Bt‐mMnSOD) was compared after transferring MEAM1 and Asia II 3 whiteflies from favorable (cotton) to unfavorable host plants (tobacco). On cotton, both CuZnSOD genes were expressed at a higher level in MEAM1 compared with Asia II 3. Interestingly, after transferring onto tobacco, the expression of Bt‐ecCuZnSOD was significantly induced in Asia II 3 but not in MEAM1. On the other hand, while Bt‐mMnSOD was expressed equally in both species on cotton, Bt‐mMnSOD messenger RNA was up‐regulated in MEAM1 on tobacco. Consistently, enzymatic activity assays of CuZnSOD and MnSOD demonstrated that CuZnSOD might play an important protective role against oxidative stress in Asia II 3, whereas MnSOD activation was critical for MEAM1 whiteflies during host adaptation. Taken together, our results suggest that the successful invasion of MEAM1 is correlated with its constitutive high activity of CuZnSOD and inducible expression of MnSOD under stress conditions.
Planktonic foraminifera as bio‐indicators for monitoring the climatic changes that have occurred over the past 2000 years in the southeastern Tyrrhenian Sea
Authors: LIRER Fabrizio , SPROVIERI Mario , VALLEFUOCO Mattia , FERRARO Luciana , PELOSI Nicola , GIORDANO Laura , CAPOTONDI Lucilla
Published: December 2013

A high‐resolution integrated study has been performed in a super‐expanded marine record (sedimentation rate spanning from 11 cm/100 years to 20 cm/100 years) from the continental shelf area of the southeastern Tyrrhenian Sea. Planktonic foraminiferal distribution illustrates 6 major environmental changes during the past 2000 years: (i) the Roman Period–Dark Age transition (from herbivorous‐opportunistic to carnivorous species); (ii) the Dark Age–MCA transition (from carnivorous to herbivorous‐opportunistic species); (iii) the Medieval Classic Anomaly–Little Ice Age transition (a further and definitive change from carnivorous to herbivorous‐opportunistic species); (iv) the period during the Maunder event between approximately 1720 AD and 1740 AD (turnover from the carnivorous planktonic foraminifer Globigerinodes ruber to the herbivorous‐opportunistic planktonic foraminifer Turborotalita quinqueloba); (v) the Industrial Period (dominance of herbivorous‐opportunistic planktonic foraminifera); and (vi) the Modern Warm Period at approximately 1940 AD (the last turnover in favor of herbivorous‐opportunistic planktonic foraminifers, associated with an increase in benthic foraminifera). Our studies lead us to link this latter feature to an anthropogenic impact associated with the damming of Sele River (Salerno Gulf) at 1934 AD, which induced a change in the sediment input with a strong decrease in coarse‐grained fraction and a probable alteration in nutrient supply. The δ18OG. ruber record of the past 2000 years shows the alternation of warm/wet and cold/dry events related to the Roman Period, the Dark Age, the Medieval Classic Anomaly, the Little Ice Age, the Industrial Period and the Modern Warm Period. The 5 evident δ18OG. ruber oscillations (between approximately 1325 AD and 1940 AD) coincide with the 5 minima in the solar activity record (Wolf, Spörer, Maunder, Dalton and Damon events).
Invasive black spiny‐tailed iguanas (Ctenosaura similis) on Gasparilla Island, Florida, USA
Authors: AVERY Michael L. , TILLMAN Eric A. , SPURFELD Conny , ENGEMAN Richard M. , MACIEJEWSKI Kelin P. , BROWN Jessica D. , FETZER Emily A.
Published: December 2013

The native range of Ctenosaura similis extends from southern Mexico through Panama. From an initial introduction of 3 animals in 1979, the species now numbers in the thousands on Gasparilla Island in southwest Florida. In response to complaints of property damage from residents and threats to native species, local officials and the US Department of Agriculture Wildlife Services began a removal program in 2008. Through 2011, trappers removed 9467 ctenosaurs. The number removed declined from 32 iguanas/day in 2008 to 1.9 iguanas/day in 2011 despite no easing of the control effort. We necropsied 2757 ctenosaurs to document aspects of their natural history. Females outnumbered males overall, although the largest size class (>300 mm snout–vent length) included 32 males and just 2 females. Reproduction was seasonal. We found oviducal eggs in females from early Apr to early Jun, approximately 2 months later than C. similis in its native range. We trapped hatchlings from late Jul to early Oct coincident with the summer rainy season. Clutch size increased with female body size, with 62 being the largest clutch size recorded. In general, the biology of the invasive population on Gasparilla Island resembles native C. similis populations in Central America, except for the lack of large individuals. We suggest that shorter day length and colder temperatures create environmental conditions that are suboptimal for individual growth compared to those in the native range.
Seed traits and taxonomic relationships determine the occurrence of mutualisms versus seed predation in a tropical forest rodent and seed dispersal system
Authors: WANG Zhenyu , CAO Lin , ZHANG Zhibin
Published: December 2013

Although many studies have been carried out on plant–animal mutualistic assemblages, the roles of functional traits and taxonomy in determining both whether interactions involve mutualisms or predation and the structure of such assemblages are unclear. We used semi‐natural enclosures to quantitatively assess the interaction strengths between seeds of 8 sympatric tree species and 4 rodent species in a tropical forest in Xishuangbanna, Yunnan, Southwest China. We found 2 clusters of species in the seed–rodent network represented by 2 genera in the Fagaceae (Castanopsis, Lithocarpus). Compared to seeds of 3 Castanopsis species, seeds with heavy weight, hard coat or caloric content (including 3 Lithocarpus species) were eaten less and more frequently hoarded by rodents. In turn, hoarded seeds showed less predation and more mutualism with rodents. Our results suggest that seed traits significantly affected the hoarding behavior of rodents, and, consequently, the occurrence of mutualisms and predation as well as assemblage structure in the plant–animal seed dispersal system. Taxonomically‐related species with similar seed traits as functional groups belong to the same substructures in the assemblage. Our results indicate that both seed traits and taxonomic relationships may simplify thinking about seed dispersal systems by helping to elucidate whether interactions are likely to be dominated by predation or mutualism.
Factors associated with withdrawal of the anti‐TNFα biologics in the treatment of rheumatic diseases: data from the Hong Kong Biologics Registry
Authors: Mok Chi Chiu , Chan Ka Yan , Lee Ka Lai , Tam Lai Shan , Lee Ka Wing ,   the Hong Kong Society of Rheumatology
Published: December 2013

Objectives

To study the factors associated with withdrawal of the and tumor necrosis factor alpha (anti‐TNFα) biologics in the treatment of rheumatic diseases.

Method

Data from the Hong Kong Biologics Registry were retrieved. The cumulative rates of withdrawal of different biological agents were studied by Kaplan–Meier plot and the incidence of serious adverse events (SAEs) was calculated. Factors associated with the withdrawal of the anti‐TNFα agents were studied by Cox regression.

Results

Between 2005 and 2013, 2059 courses of biologics were used in 1345 patients. After 3454 patient‐years, 1171 (57%) courses were terminated because of clinical inefficacy (38.1%), SAEs (22.3%) and financial reasons (15.9%). The most frequent SAEs (per 100‐patient‐years) were allergy (2.90), serious infections (1.34), tuberculosis (0.93) and infusion/injection site reaction (0.75). Among the anti‐TNFα agents, the cumulative probability of drug withdrawal for either inefficacy or SAEs in 5 years was highest with infliximab (IFX) (64.5%), followed by etanercept (ETN) (44.2%) and adalimumab (ADA) (36.9%). The incidence of serious infections and tuberculosis (per 100 patient‐years) for IFX, ETN and ADA users was 1.99, 0.85 and 0.63; and 1.68, 0.43 and 0.85, respectively. Infusion/injection site reaction was highest with IFX (1.38/100 patient‐years). Cox regression revealed increasing age, female sex, not having a diagnosis of spondyloarthritis (SpA) and IFX use were significantly associated with drug withdrawal for either inefficacy or SAEs. Rheumatoid arthritis (RA) had the highest hazard ratio for drug withdrawal but SpA was favorable for drug retention, after adjustment for age, sex, disease duration and the choice of anti‐TNFα agents.

Conclusions

In our registry, the retention rate of the anti‐TNFα agents was lowest but the incidence of tuberculosis, serious infections and infusion reaction was highest with IFX. Older female patients with RA and the use of IFX were independently associated with drug withdrawal.
Gaining views from pupils with autism about their participation in drama classes
Authors: Loyd Daisy
Published: December 2013

Accessible Summary

Pupils with autism were interviewed about their participation in drama classes.

Interview approaches were devised so that the pupils could give their views.

These approaches used different ways to engage the pupils including widgit symbols, photographs and video.

The information the pupils gave was important in building an understanding of what they take away from drama sessions.

Pupils with autism (aged 16–18) were interviewed as part of a study examining the participation of individuals with autism in drama education. This paper reflects on the approaches devised to gain views from ten pupils with autism who communicated in different ways. The procedure for gaining views from the pupils is explained, and the views they give are outlined. The pupils were able to identify aspects of drama education that they liked and did not like; share goals of drama education and communicate feelings about drama education. The views are discussed in terms of how they inform understandings of individuals with autism as well as their participation in drama education. Challenges specific to gaining views from a group of pupils with autism are considered and implications for future research presented.
The ecological and evolutionary implications of microrefugia
Authors: Mee Jonathan A. , Moore Jean‐Sébastien
Published: December 2013

Pleistocene microrefugia (or cryptic refugia) may be distinguished from macrorefugia (or conventional refugia) on the basis of two characteristics. First, microrefugia were smaller than macrorefugia and consequently supported smaller refugial populations. Second, microrefugia harboured less diverse biotic communities than macrorefugia. We propose that these characteristics have important implications for the ecology and evolution of species and populations that have a history of isolation in microrefugia. We propose four hypotheses regarding the evolution of microrefugial populations: (1) small effective population sizes associated with survival in microrefugia lead to reduced genetic diversity and influence the evolution of mating systems; (2) differences in environmental conditions between macro‐ and microrefugia lead to local adaptation; (3) reduced diversity increases ecological opportunity and promotes ecological divergence in microrefugia; and (4) reduced species diversity in microrefugia allows more specific species interactions and promotes coevolution among species. We urge biogeographers to study the evolutionary implications of isolation in microrefugia.
Candy consumption in childhood is not predictive of weight, adiposity measures or cardiovascular risk factors in young adults: the Bogalusa Heart Study
Authors: O'Neil C. E. , Nicklas T. A. , Liu Y. , Berenson G. S.
Published: December 2013

Background

There are limited data available on the longitudinal relationship between candy consumption by children on weight and other cardiovascular risk factors (CVRF) in young adults. The present study investigated whether candy consumption in children was predictive of weight and CVRF in young adults.

Methods

A longitudinal sample of children 10 years (n = 355; 61% females; 71% European‐Americans, 29% African‐Americans) who participated in cross‐sectional surveys from 1973 to 1984 (baseline) and in one of two surveys (follow‐ups) as young adults [19–38 years; mean (SD) = 23.6 (2.6) years] in Bogalusa, LA, were studied. Dietary data were collected using 24‐h dietary recalls at baseline and at one follow‐up survey; a food frequency questionnaire was used in the other follow‐up survey. Candy consumers were those consuming any amount of candy. Candy consumption was calculated (g day–1) from baseline 24‐h dietary recalls, and was used as a covariate in the adjusted linear mixed models. Dependent variables included body mass index (BMI) and CVRF measured in young adults.

Results

At baseline, 92% of children reported consuming candy [46 (45) g day–1]; the percentage decreased to 67% [20 (30) g day–1] at follow‐up. No longitudinal relationship was shown between baseline candy consumption and BMI or CVRF in young adults, suggesting that candy consumption was not predictive of health risks later in life.

Conclusions

The consumption of nutrient rich foods consistent with dietary recommendations is important, although modest amounts of candy can be added to the diet without potential adverse long‐term consequences to weight or CVRF. Additional studies are needed to confirm these results.
Private Practice of Prosthodontists in the United States: Results from the 2008 & 2011 Surveys of Prosthodontists
Authors: Nash Kent D. , Benting Douglas G.
Published: December 2013

Purpose

The purpose of this article is to review data and results from past surveys of prosthodontists sponsored and conducted by the American College of Prosthodontists. Surveys were conducted in 2002, 2005, 2008, and 2011. Selected survey results are examined for prosthodontists in private practice.

Materials and Methods

Results from past surveys of prosthodontists were statistically examined and used to estimate several characteristics of the current population of practicing prosthodontists. The selected characteristics included age, gender, number of patient visits, hours in the practice, employment of staff, referral sources, and financial conditions (e.g., gross receipts, expenses in the practice, and net income of prosthodontists). While the most recent survey was conducted in 2011, the results reported by respondents are for the previous year, 2010.

Results

The average age of a private practicing prosthodontist in 2010 reached 53 years; 26 years since graduation from dental school and 20 years since completion of residency; an average of 13 years in their current practice. Sixty percent were in solo practice. The mean number of hours per week in the practice was 35 hours, and practicing prosthodontists treated an average of 35 patient visits per week. The patient was the single largest source of referrals, while general practitioners were a close second. The largest percentage of time spent treating patients was for fixed prosthodontics (21%), which declined from a mean of 24.1% in 2007. The mean amount of gross billings in 2010 was $721,970, which was a decline from 2007. Average total practice expenses were $538,230, and the mean net earnings of prosthodontists in private practice were $238,010.

Conclusion

Changes have occurred since the last survey of prosthodontists in 2008 (with results for the year 2007). The prosthodontist private practice industry, not unlike dentistry as a whole, has undergone economic challenges that have affected the private practice of prosthodontists.
A Systematic Review of Screw‐ versus Cement‐Retained Implant‐Supported Fixed Restorations
Authors: Sherif Sami , Susarla Harlyn K. , Kapos Theodoros , Munoz Deborah , Chang Brian M. , Wright Robert F.
Published: December 2013

Purpose

To systematically evaluate the survival and success of screw‐ versus cement‐retained implant crowns.

Materials and Methods

The authors performed an electronic search of nine databases using identical MeSH phrases. Systematic evaluation and data extraction of the articles from 1966 through 2007 were completed by three reviewers and two clinical academicians. The major outcome variable was implant or crown loss, and the minor outcome variables were screw loosening, decementation, and porcelain fracture. Random effects Poisson models were used to analyze the failure and complication rates.

Results

The initial search produced 26,582 articles. Of these, 577 titles and subsequently 295 abstracts were available for evaluation, with 81 full texts meeting the criteria for review. Data were extracted from 23 level one and two research studies. Fleiss’ kappa interevaluator agreement ranged from almost perfect to moderate. Major failures included 0.71 screw‐retained and 0.87 cement‐retained failures per 100 years. Minor failures included 3.66 screw loosenings, 2.54 decementations, and 0.46 porcelain fractures per 100 years.

Conclusion

There is no significant difference between cement‐ and screw‐retained restorations for major and minor outcomes with regard to implant survival or crown loss. This is important data, as clinicians use both methods of restoration, and neither is a form of inferior care.
Responders vs clinical response: a critical analysis of data from linaclotide phase 3 clinical trials in IBS‐C
Authors: Lacy B. E. , Lembo A. J. , MacDougall J. E. , Shiff S. J. , Kurtz C. B. , Currie M. G. , Johnston J. M.
Published: December 2013

Background

US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome‐C (IBS‐C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health‐care practitioners to assess clinical response has not been determined. We analyzed pooled IBS‐C linaclotide trial data to evaluate clinically significant responses in linaclotide‐treated patients who did not meet the FDA responder definition.

Methods

Percentages of FDA non‐responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS‐C trials.

Key Results

1602 IBS‐C patients enrolled; 34% of linaclotide‐treated and 17% of placebo‐treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non‐responders at week 12, 63% of linaclotide‐treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo‐treated patients. For stool frequency, 62% of linaclotide‐treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo‐treated patients. For global IBS symptoms, 65% of linaclotide‐treated patients reported at least some IBS‐symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively.

Conclusions & Inferences

Most linaclotide‐treated IBS‐C patients who were FDA non‐responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom‐specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS‐C therapies.
Efficacy, Safety, and Tolerability of Telcagepant in the Treatment of Acute Migraine: A meta‐Analysis
Authors: Cui Xiao‐ping , Ye Jian‐xin , Lin Hang , Mu Jun‐shan , Lin Min
Published: December 2013

Although triptans are widely used for treating acute migraine, they are contraindicated or not effective in a large proportion of patients. Hence, alternative treatments are needed. Calcitonin gene–related peptide receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. A meta‐analysis of the efficacy of telcagepant vs. placebo and triptans (zolmitriptan or rizatriptan) was performed. Randomized controlled trials were indentified from databases using the following search terms: migraine; calcitonin gene‐related peptide; calcitonin gene‐related peptide receptor antagonists; efficacy; safety, and telcagepant. The primary outcome measure was pain freedom 2 hours after first treatment. The secondary outcome measure was pain relief 2 hours after first treatment. Eight trials were included in the meta‐analysis (telcagepant = 4011 participants). The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27–3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56–0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18–2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (odds ratio = 0.76, 95% confidence interval = 0.57–1.01, P = 0.061). These findings indicate that telcagepant can be effective for treating acute migraine. Calcitonin gene‐related peptide receptor antagonists represent a potentially important alternative means of treating acute migraine.
Risk Management of Domino Effects Considering Dynamic Consequence Analysis
Authors: Khakzad Nima , Khan Faisal , Amyotte Paul , Cozzani Valerio
Published: December 2013

Domino effects are low‐probability high‐consequence accidents causing severe damage to humans, process plants, and the environment. Because domino effects affect large areas and are difficult to control, preventive safety measures have been given priority over mitigative measures. As a result, safety distances and safety inventories have been used as preventive safety measures to reduce the escalation probability of domino effects. However, these safety measures are usually designed considering static accident scenarios. In this study, we show that compared to a static worst‐case accident analysis, a dynamic consequence analysis provides a more rational approach for risk assessment and management of domino effects. This study also presents the application of Bayesian networks and conflict analysis to risk‐based allocation of chemical inventories to minimize the consequences and thus to reduce the escalation probability. It emphasizes the risk management of chemical inventories as an inherent safety measure, particularly in existing process plants where the applicability of other safety measures such as safety distances is limited.
A new species ofPseudotettigoniaZeuner (Orthoptera:Tettigoniidae) with an intact stridulatory field and reexamination of the subfamilyPseudotettigoniinae
Authors: GREENWALT DALE E. , RUST JES
Published: December 2013

Pseudotettigonia leonasp.n.is described from a single left forewing collected from theMiddleEoceneKishenehnFormation in northwesternMontana, U.S.A.P. leonais the second of only two fossil macropterousTettigoniidae that preserve an intact stridulatory apparatus. The subfamilyPseudotettigoniinae is reexamined. The specific epithetbriceiis assigned to thelateMiocene fossil tettigoniidTettigonia briceisp.n., originally described as the extantTettigonia viridissima.

This published work has been registered in ZooBank,http://zoobank.org/urn:lsid:zoobank.org:pub:E69E83CE‐9046‐4BBD‐AA11‐E0AD0C382700.
Governance and Globalisation
Authors: Berden Koen , Bergstrand Jeffrey H. , van Etten Eva
Published: December 2013

Unlike the large literature on ‘democracy and trade’, there is a much smaller literature on the effect of the level of democracy in a nation on the level of its foreign direct investment (FDI) inflow. These few studies reveal mixed empirical results, and surprisingly only one study has examined bilateral FDI flows. Moreover, few of these studies use multiple governance indicators separating the ‘pluralism’ effect of democratic institutions from the ‘good governance’ effect, there are no studies on democratic institutions’ various effects on the level of FDI relative to trade, and there are no studies of democratic institutions’ various effects on the selection of countries into FDI. We focus on three contributions. First, we examine the simultaneous effects of the World Bank's (six) Worldwide Governance Indicators (WGIs) – which allow separating the effects of pluralism from those of five other good governance measures – on bilateral trade, FDI and FDI relative to trade using state‐of‐the‐art gravity specifications. Second, we find strong evidence that – after accounting for host governments’ effectiveness in various roles of good governance – a higher level of pluralism as measured by the WGIs’ Voice and Accountability Index reduces trade levels, likely by increasing the ‘voice’ of more protectionist less‐skilled workers, but not FDI levels. Moreover, we find qualitatively different effects of other WGIs – such as political stability – on trade versus FDI flows. Third, we account for firm heterogeneity alongside a large number of zeros in bilateral FDI flows using recent advances in gravity modelling. We distinguish between the (country) intensive and extensive margins and show that pluralism affects FDI inflows negatively at the intensive margin, but positively at the extensive margin.
Cross‐Sectional Serosurvey of Avian Influenza Antibodies Presence in Domestic Ducks of Kathmandu, Nepal
Authors: Karki S. , Lupiani B. , Budke C. M. , Manandhar S. , Ivanek R.
Published: December 2013

Kathmandu, Nepal has been classified as a high‐risk area for highly pathogenic avian influenza (HPAI) by the Nepali Government. While ducks have an important role in the transmission of avian influenza viruses (AIV), including HPAI, seroprevalence of antibodies to AIV in domestic ducks of Kathmandu has never been assessed. The objectives of this study were (i) to estimate the prevalence of seroconversion to AIV in domestic ducks in major duck‐raising areas of Kathmandu and (ii) to assess the effect of age, sex, presence of swine and the number of ducks on the farm on the carriage of antibodies to AIV in these ducks. From April through July of 2011, a cross‐sectional study was conducted and a total of 310 ducks in the major duck‐raising areas of Kathmandu were sampled. The estimated prevalence of AIV antibodies was 27.2% [95% confidence interval (CI): 24.6–29.5]. Of 62 enrolled farms, 42% had at least one seropositive duck. Half of the enrolled farms also kept pigs of which 52% had at least one seropositive duck. Bivariate analysis indicated association between ducks' seroconversion to AIV and their age, sex and farm size. However, the final multivariable model, after controlling for clustering of ducks within farms, identified age as the only significant risk factor. Based on this model, ducks older than 1 year of age were more likely to be seropositive compared to ducks <6 months of age [odds ratio = 2.17 (1.07–4.39)]. These results provide baseline information about the AIV seroprevalence in domestic ducks in the major duck‐raising areas of Kathmandu and identify a high‐risk group that can be targeted in surveillance activities. Future studies should be conducted to differentiate the subtypes of AIV present among domestic ducks in Kathmandu, with particular interest in the presence of HPAI viruses.
New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World
Authors: Drawz Sarah M. , Papp-Wallace Krisztina M. , Bonomo Robert A.
Published: December 2013

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
Activities of Tobramycin and Polymyxin E against Pseudomonas aeruginosa Biofilm-Coated Medical Grade Endotracheal Tubes
Authors: Tarquinio Keiko , Confreda Kelsey , Shurko James , LaPlante Kerry
Published: December 2013

Indwelling medical devices have become a major source of nosocomial infections, especially
Pseudomonas aeruginosa
infections, which remain the most common cause of ventilator-associated pneumonia (VAP) in neonates and children. Using medical grade polyvinyl chloride endotracheal tubes (ETTs), the activity of tobramycin and polymyxin E was quantified in a simulated prevention and treatment static time-kill model using biofilm-forming
P. aeruginosa
. The model simulated three clinical conditions: (i) planktonic bacteria grown in the presence of antibiotics (tobramycin and polymyxin E) without ETTs, (ii) planktonic bacteria grown in the presence of
P. aeruginosa
, antibiotic, and ETTs (simulating prevention), and (iii) a 24-h-formed
P. aeruginosa
biofilm grown on ETTs prior to antibiotic exposure (simulating treatment). In the model simulating “prevention” (conditions 1 and 2 above), tobramycin alone or in combination with polymyxin E was more bactericidal than polymyxin E alone at 24 h using a concentration of greater than 2 times the MIC. However, after a 24-h-old biofilm was allowed to form on the ETTs, neither monotherapy nor combination therapy over 24 h exhibited bactericidal or bacteriostatic effects. Against the same pathogens, tobramycin and polymyxin E, alone or in combination, exhibited bactericidal activity prior to biofilm attachment to the ETTs; however, no activity was observed once biofilm formed on ETTs. These findings support surveillance culturing to identify pathogens for a rapid and targeted approach to therapy, especially when
P. aeruginosa
is a potential pathogen.
Evaluation of DNA Primase DnaG as a Potential Target for Antibiotics
Authors: Kuron Aneta , Korycka-Machala Malgorzata , Brzostek Anna , Nowosielski Marcin , Doherty Aidan , Dziadek Bozena , Dziadek Jaroslaw
Published: December 2013

Mycobacteria contain genes for several DNA-dependent RNA primases, including
dnaG
, which encodes an essential replication enzyme that has been proposed as a target for antituberculosis compounds. An
in silico
analysis revealed that mycobacteria also possess archaeo-eukaryotic superfamily primases (AEPs) of unknown function. Using a homologous recombination system, we obtained direct evidence that wild-type
dnaG
cannot be deleted from the chromosome of
Mycobacterium smegmatis
without disrupting viability, even in backgrounds in which mycobacterial AEPs are overexpressed. In contrast, single-deletion AEP mutants or mutants defective for all four identified
M. smegmatis
AEP genes did not exhibit growth defects under standard laboratory conditions. Deletion of native
dnaG
in
M. smegmatis
was tolerated only after the integration of an extra intact copy of the
M. smegmatis
or
Mycobacterium tuberculosis
dnaG
gene, under the control of chemically inducible promoters, into the
attB
site of the chromosome.
M. tuberculosis
and
M. smegmatis
DnaG proteins were overproduced and purified, and their primase activities were confirmed using radioactive RNA synthesis assays. The enzymes appeared to be sensitive to known inhibitors (suramin and doxorubicin) of DnaG. Notably,
M. smegmatis
bacilli appeared to be sensitive to doxorubicin and resistant to suramin. The growth and survival of conditional mutant mycobacterial strains in which DnaG was significantly depleted were only slightly affected under standard laboratory conditions. Thus, although DnaG is essential for mycobacterial viability, only low levels of protein are required for growth. This suggests that very efficient inhibition of enzyme activity would be required for mycobacterial DnaG to be useful as an antibiotic target.
Genomics of KPC-Producing Klebsiella pneumoniae Sequence Type 512 Clone Highlights the Role of RamR and Ribosomal S10 Protein Mutations in Conferring Tigecycline Resistance
Authors: Villa Laura , Feudi Claudia , Fortini Daniela , García-Fernández Aurora , Carattoli Alessandra
Published: December 2013

Full genome sequences were determined for five
Klebsiella pneumoniae
strains belonging to the sequence type 512 (ST512) clone, producing KPC-3. Three strains were resistant to tigecycline, one showed an intermediate phenotype, and one was susceptible. Comparative analysis performed using the genome of the susceptible strain as a reference sequence identified genetic differences possibly associated with resistance to tigecycline. Results demonstrated that mutations in the
ramR
gene occurred in two of the three sequenced strains. Mutations in RamR were previously demonstrated to cause overexpression of the AcrAB-TolC efflux system and were implicated in tigecycline resistance in
K. pneumoniae
. The third strain showed a mutation located at the vertex of a very well conserved loop in the S10 ribosomal protein, which is located in close proximity to the tigecycline target site in the 30S ribosomal subunit. This mutation was previously shown to be associated with tetracycline resistance in
Neisseria gonorrhoeae
. A PCR-based approach was devised to amplify the potential resistance mechanisms identified by genomics and applied to two additional ST512 strains showing resistance to tigecycline, allowing us to identify mutations in the
ramR
gene.
Role of P-Glycoprotein in the Distribution of the HIV Protease Inhibitor Atazanavir in the Brain and Male Genital Tract
Authors: Robillard Kevin R. , Chan Gary N. Y. , Zhang Guijin , la Porte Charles , Cameron William , Bendayan Reina
Published: December 2013

The blood-testis barrier and blood-brain barrier are responsible for protecting the male genital tract and central nervous system from xenobiotic exposure. In HIV-infected patients, low concentrations of antiretroviral drugs in cerebrospinal fluid and seminal fluid have been reported. One mechanism that may contribute to reduced concentrations is the expression of ATP-binding cassette drug efflux transporters, such as P-glycoprotein (P-gp). The objective of this study was to investigate
in vivo
the tissue distribution of the HIV protease inhibitor atazanavir in wild-type (WT) mice, P-gp/breast cancer resistance protein (Bcrp)-knockout (
Mdr1a
−/−
,
Mdr1b
−/−
, and
Abcg2
−/−
triple-knockout [TKO]) mice, and Cyp3a
−/−
(Cyp) mice. WT mice and Cyp mice were pretreated with a P-gp/Bcrp inhibitor, elacridar (5 mg/kg of body weight), and the HIV protease inhibitor and boosting agent ritonavir (2 mg/kg intravenously [i.v.]), respectively. Atazanavir (10 mg/kg) was administered i.v. Atazanavir concentrations in plasma (
C
plasma
), brain (
C
brain
), and testes (
C
testes
) were quantified at various times by liquid chromatography-tandem mass spectrometry. In TKO mice, we demonstrated a significant increase in atazanavir
C
brain
/
C
plasma
(5.4-fold) and
C
testes
/
C
plasma
(4.6-fold) ratios compared to those in WT mice (
P
< 0.05). Elacridar-treated WT mice showed a significant increase in atazanavir
C
brain
/
C
plasma
(12.3-fold) and
C
testes
/
C
plasma
(13.5-fold) ratios compared to those in vehicle-treated WT mice. In Cyp mice pretreated with ritonavir, significant (
P
< 0.05) increases in atazanavir
C
brain
/
C
plasma
(1.8-fold) and
C
testes
/
C
plasma
(9.5-fold) ratios compared to those in vehicle-treated WT mice were observed. These data suggest that drug efflux transporters, i.e., P-gp, are involved in limiting the ability of atazanavir to permeate the rodent brain and genital tract. Since these transporters are known to be expressed in humans, they could contribute to the low cerebrospinal and seminal fluid antiretroviral concentrations reported in the clinic.
Iron-Induced Virulence of Salmonella enterica Serovar Typhimurium at the Intestinal Epithelial Interface Can Be Suppressed by Carvacrol
Authors: Kortman Guus A. M. , Roelofs Rian W. H. M. , Swinkels Dorine W. , de Jonge Marien I. , Burt Sara A. , Tjalsma Harold
Published: December 2013

Oral iron therapy can increase the abundance of bacterial pathogens, e.g.,
Salmonella
spp., in the large intestine of African children. Carvacrol is a natural compound with antimicrobial activity against various intestinal bacterial pathogens, among which is the highly prevalent
Salmonella enterica
serovar Typhimurium. This study aimed to explore a presumed interaction between carvacrol and bacterial iron handling and to assess the potential of carvacrol in preventing the increase of bacterial pathogenicity during high iron availability.
S
. Typhimurium was cultured with increasing concentrations of iron and carvacrol to study the effects of these combined interventions on growth, adhesion to intestinal epithelial cells, and iron uptake/influx in both bacterial and epithelial cells. In addition, the ability of carvacrol to remove iron from the high-affinity ligand transferrin and an Fe-dye complex was examined. Carvacrol retarded growth of
S
. Typhimurium at all iron conditions. Furthermore, iron-induced epithelial adhesion was effectively reduced by carvacrol at high iron concentrations. The reduction of growth and virulence by carvacrol was not paralleled by a change in iron uptake or influx into
S
. Typhimurium. In contrast, bioavailability of iron for epithelial cells was moderately decreased under these conditions. Further, carvacrol was shown to lack the properties of an iron binding molecule; however, it was able to weaken iron-ligand interactions by which it may possibly interfere with bacterial virulence. In conclusion, our
in vitro
data suggest that carvacrol has the potential to serve as a novel dietary supplement to prevent pathogenic overgrowth and colonization in the large intestine during oral iron therapy.
In Vitro
Activity of Solithromycin against Erythromycin-Resistant Streptococcus agalactiae
Authors: Piccinelli Giorgio , Fernandes Prabhavathi , Bonfanti Carlo , Caccuri Francesca , Caruso Arnaldo , De Francesco Maria Antonia
Published: December 2013

The
in vitro
antibacterial activity of solithromycin (CEM-101) against macrolide-resistant isolates (
n
= 62) of
Streptococcus agalactiae
(group B streptococcus [GBS]) was determined. Phenotypic characterization of macrolide-resistant strains was performed by double-disc diffusion testing. A multiplex PCR was used to identify the
erm
(B),
erm
(TR), and
mef
(A/E) genes, capsular genotypes, and alpha-like (Alp) protein genes from the GBS strains. Determination of MIC was carried out using the microdilution broth method. The Etest method was used for penicillin, azithromycin, clarithromycin, and erythromycin. Solithromycin had a MIC
50
of ≤0.008 μg/ml and a MIC
90
of 0.015 μg/ml against macrolide-susceptible
S. agalactiae
. These MICs were lower than those displayed by penicillin (MIC
50
of 0.032 μg/ml and MIC
90
of 0.047 μg/ml), the antibiotic agent of choice for prophylaxis and treatment of GBS infections. Against macrolide-resistant
S. agalactiae
, solithromycin had a MIC
50
of 0.03 μg/ml and a MIC
90
of 0.125 μg/ml. Against
erm
(B) strains, solithromycin had a MIC
50
of 0.03 μg/ml and a MIC
90
of 0.06 μg/ml, while against
mef
(A) strains, it had a MIC
50
of 0.03 μg/ml and a MIC
90
of 0.125 μg/ml. Most erythromycin-resistant GBS strains were of serotype V (64.5%) and associated significantly with
alp2-3
. Moreover, a statistically significant association was observed between the constitutive macrolide-lincosamide-streptogramin B resistance (cMLS
B
) phenotype and the
erm
(B) gene-carrying strains, the
alp2-3
gene and the M phenotype, and the
mef
(A/E) gene and
epsilon
. Overall, our results show that solithromycin had lower or similar MICs than penicillin and potent activity against macrolide-resistant strains independent of their genotype or phenotype, representing a valid therapeutic alternative where β-lactams cannot be used.
Substituted Diphenyl Ethers as a Novel Chemotherapeutic Platform against Burkholderia pseudomallei
Authors: Cummings Jason E. , Beaupre Adam J. , Knudson Susan E. , Liu Nina , Yu Weixuan , Neckles Carla , Wang Hui , Khanna Avinash , Bommineni Gopal R. , Trunck Lily A. , Schweizer Herbert P. , Tonge Peter J. , Slayden Richard A.
Published: December 2013

Identification of a novel class of anti-
Burkholderia
compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. The FabI enoyl-ACP reductase in
Burkholderia
is an underexploited target that presents an opportunity for development of a new class of inhibitors. A library of substituted diphenyl ethers was used to identify FabI1-specific inhibitors for assessment in
Burkholderia pseudomallei ex vivo
and murine efficacy models. Active FabI1 inhibitors were identified in a two-stage format consisting of percent inhibition screening and MIC determination by the broth microdilution method. Each compound was evaluated against the
B. pseudomallei
1026b (efflux-proficient) and Bp400 (efflux-compromised) strains.
In vitro
screening identified candidate substituted diphenyl ethers that exhibited MICs of less than 1 μg/ml, and enzyme kinetic assays were used to assess potency and specificity against the FabI1 enzyme. These compounds demonstrated activity in a
Burkholderia ex vivo
efficacy model, and two demonstrated efficacy in an acute
B. pseudomallei
mouse infection model. This work establishes substituted diphenyl ethers as a suitable platform for development of novel anti-
Burkholderia
compounds that can be used for treatment of melioidosis.
Disruption of Biofilm Formation by the Human Pathogen Acinetobacter baumannii Using Engineered Quorum-Quenching Lactonases
Authors: Chow Jeng Yeong , Yang Yuanyong , Tay Song Buck , Chua Kim Lee , Yew Wen Shan
Published: December 2013

Acinetobacter baumannii
is a major human pathogen associated with multidrug-resistant nosocomial infections; its virulence is attributed to quorum-sensing-mediated biofilm formation, and disruption of biofilm formation is an attractive antivirulence strategy. Here, we report the first successful demonstration of biofilm disruption in a clinical isolate of
A. baumannii
S1, using a quorum-quenching lactonase obtained by directed evolution; this engineered lactonase significantly reduced the biomass of
A. baumannii
-associated biofilms, demonstrating the utility of this antivirulence strategy.
Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012
Authors: Sader Helio S. , Castanheira Mariana , Flamm Robert K. , Farrell David J. , Jones Ronald N.
Published: December 2013

The activities of the novel β-lactam–β-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli—8,640
Enterobacteriaceae
, 1,967
Pseudomonas aeruginosa
, and 321
Acinetobacter
sp. isolates—were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% of
Enterobacteriaceae
strains were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotype
Escherichia coli
and
Klebsiella pneumoniae
, meropenem-nonsusceptible (MIC ≥ 2 μg/ml)
K. pneumoniae
, and ceftazidime-nonsusceptible
Enterobacter cloacae
. Among ESBL-phenotype
K. pneumoniae
strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Among
P. aeruginosa
strains, 96.9% were inhibited at a ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible
P. aeruginosa
(MIC
50
/MIC
90
, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml).
Acinetobacter
spp. (ceftazidime-avibactam MIC
50
/MIC
90
, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as
K. pneumoniae
carbapenemase (KPC)-producing
Enterobacteriaceae
and meropenem-nonsusceptible
P. aeruginosa
.