bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance Analysis of the Hepatitis C Virus NS5A Inhibitor BMS-790052 in an
In Vitro
Replicon System
Authors: Fridell Robert A. , Qiu Dike , Wang Chunfu , Valera Lourdes , Gao Min 
Published: June 2010

ABSTRACT

BMS-790052 is the most potent hepatitis C virus (HCV) inhibitor reported to date, with 50% effective concentrations (EC
50
s) of ≤50 pM against genotype 1 replicons. This exceptional potency translated to rapid viral load declines in a phase I clinical study. By targeting NS5A, BMS-790052 is distinct from most HCV inhibitors in clinical evaluation. As an initial step toward correlating
in vitro
and
in vivo
resistances, multiple cell lines and selective pressures were used to identify BMS-790052-resistant variants in genotype 1 replicons. Similarities and differences were observed between genotypes 1a and 1b. For genotype 1b, L31F/V, P32L, and Y93H/N were identified as primary resistance mutations. L23F, R30Q, and P58S acted as secondary resistance substitutions, enhancing the resistance of primary mutations but themselves not conferring resistance. For genotype 1a, more sites of resistance were identified, and substitutions at these sites (M28T, Q30E/H/R, L31M/V, P32L, and Y93C/H/N) conferred higher levels of resistance. For both subtypes, combining two resistance mutations markedly decreased inhibitor susceptibility. Selection studies with a 1b/1a hybrid replicon highlighted the importance of the NS5A N-terminal region in determining genotype-specific inhibitor responses. As single mutations, Q30E and Y93N in genotype 1a conferred the highest levels of resistance. For genotype 1b, BMS-790052 retained subnanomolar potency against all variants with single amino acid substitutions, suggesting that multiple mutations will likely be required for significant
in vivo
resistance in this genetic background. Importantly, BMS-790052-resistant variants remained fully sensitive to alpha interferon and small-molecule inhibitors of HCV protease and polymerase.
Impact of Cotrimoxazole on Carriage and Antibiotic Resistance of
Streptococcus pneumoniae
and
Haemophilus influenzae
in HIV-Infected Children in Zambia
Authors: Mwenya Darlington M. , Charalambous Bambos M. , Phillips Patrick P. J. , Mwansa James C. L. , Batt Sarah L. , Nunn Andrew J. , Walker Sarah , Gibb Diana M. , Gillespie Stephen H. 
Published: June 2010

ABSTRACT

This is a substudy of a larger randomized controlled trial on HIV-infected Zambian children, which revealed that cotrimoxazole prophylaxis reduced morbidity and mortality despite a background of high cotrimoxazole resistance. The impact of cotrimoxazole on the carriage and antibiotic resistance of
Streptococcus pneumoniae
and
Haemophilus influenzae
as major causes of childhood mortality in HIV-infected children was investigated since these are unclear. Representative nasopharyngeal swabs were taken prior to randomization for 181 of 534 children (92 on cotrimoxazole and 89 on placebo). Bacterial identification and antibiotic susceptibility were performed by routine methods. Due to reduced mortality, prophylactic cotrimoxazole increased the median time from randomization to the last specimen from 48 to 56 months (
P
= 0.001). The carriage of
H. influenzae
was unaltered by cotrimoxazole. Carriage of
S. pneumoniae
increased slightly in both arms but was not statistically significant in the placebo arm. In
S. pneumoniae
switching between carriage and no carriage in consecutive pairs of samples was unaffected by cotrimoxazole (
P
= 0.18) with a suggestion that the probability of remaining carriage free was lower (
P
= 0.10). In
H. influenzae
cotrimoxazole decreased switching from carriage to no carriage (
P
= 0.02). Cotrimoxazole resistance levels were higher in postbaseline samples in the cotrimoxazole arm than in the placebo arm (
S. pneumoniae
,
P
< 0.0001;
H. influenzae
,
P
= 0.005). Cotrimoxazole decreased switching from cotrimoxazole resistance to cotrimoxazole sensitivity in
S. pneumoniae
(
P
= 0.002) and reduced the chance of
H. influenzae
remaining cotrimoxazole sensitive (
P
= 0.05). No associations were observed between the percentage of CD4 (CD4%), the change in CD4% from baseline, child age at date of specimen, child gender, or sampling month with carriage of either pathogen.
Serum and Cerebrospinal Fluid Levels of Colistin in Pediatric Patients
Authors: Antachopoulos Charalampos , Karvanen Matti , Iosifidis Elias , Jansson Britt , Plachouras Diamantis , Cars Otto , Roilides Emmanuel 
Published: June 2010

ABSTRACT

Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 1 months to 14 years receiving intravenous colistimethate sodium (60,000 to 225,000 IU/kg of body weight/day). Only in one of five courses studied (a 14-year-old receiving 225,000 IU/kg/day) did serum concentrations exceed the 2 μg/ml CLSI/EUCAST breakpoint defining susceptibility to colistin for
Pseudomonas
and
Acinetobacter.
CSF colistin concentrations were <0.2 μg/ml but increased in the presence of meningitis (∼0.5 μg/ml or 34 to 67% of serum levels).
A Pathoadaptive Deletion in an EnteroaggregativeEscherichia coliOutbreak Strain Enhances Virulence in aCaenorhabditis elegansModel
Authors: Hwang Jennifer , Mattei Lisa M. , VanArendonk Laura G. , Meneely Philip M. , Okeke Iruka N. 
Published: June 2010

ABSTRACTEnteroaggregativeEscherichia coli(EAEC) strains are important diarrheal pathogens. EAEC strains are defined by their characteristic stacked-brick pattern of adherence to epithelial cells but show heterogeneous virulence and have different combinations of adhesin and toxin genes. Pathoadaptive deletions in the lysine decarboxylase (cad) genes have been noted among hypervirulentE. colisubtypes ofShigellaand enterohemorrhagicE. coli. To test the hypothesis thatcaddeletions might account for heterogeneity in EAEC virulence, we developed aCaenorhabditis eleganspathogenesis model. Well-characterized EAEC strains were shown to colonize and killC. elegans, and differences in virulence could be measured quantitatively. Of 49 EAEC strains screened for lysine decarboxylase activity, 3 tested negative. Most notable is isolate 101-1, which was recovered in Japan, from the largest documented EAEC outbreak. EAEC strain 101-1 was unable to decarboxylate lysinein vitrodue to deletions incadAandcadC, which, respectively, encode lysine decarboxylase and a transcriptional activator of thecadABgenes. Strain 101-1 was significantly more lethal toC. elegansthan control strain OP50. Lethality was attenuated when the lysine decarboxylase defect was complemented from a multicopy plasmid and in single copy. In addition, restoring lysine decarboxylase function produced derivatives of 101-1 deficient in aggregative adherence to cultured human epithelial cells. Lysine decarboxylase inactivation is pathoadapative in an important EAEC outbreak strain, and deletion ofcadgenes could produce hypervirulent EAEC lineages in the future. These results suggest that loss, as well as gain, of genetic material can account for heterogeneous virulence among EAEC strains.
Transforming Growth Factor β and CD25 Are Important for Controlling Systemic Dissemination followingYersiniaenterocoliticaInfection of the Gut
Authors: Zhong Youmin , Cantwell Angelene , Dube Peter H. 
Published: June 2010

ABSTRACTInfection of the gut by invasive bacterial pathogens leads to robust inflammatory responses that if left unchecked can lead to autoimmune disease and other sequelae. How the immune system controls inflammation and limits collateral damage to the host during acute bacterial infection is poorly understood. Here, we report that antibody-mediated neutralization of transforming growth factor β (TGF-β) prior to infection with the model enteric pathogenYersinia enterocoliticareduces the mean time to death by 1 day (P= 0.001), leads to rapid colonization of the liver and lung, and is associated with exacerbation of inflammatory histopathology. DuringYersinia enterocoliticainfection CD4+cells are the source ofde novoTGF-β transcription in the Peyer's patches, mesenteric lymph nodes, and spleen. Correspondingly there is both antigen-specific and -independent expansion of CD4+CD25+Foxp3+and TGF-β+T-regulatory cells (T-regs) afterYersiniainfection that is reduced in ovalbumin T-cell receptor-restricted OT-II mice. Functional inactivation of CD25 by anti-CD25 treatment results in more rapid death, dissemination of the bacteria to the liver and lungs, and exacerbated inflammatory histopathology, similar to what is seen during TGF-β neutralization. Altogether, these data suggest that TGF-β produced by T-regs is important in restricting bacteria during the acute phase of invasive bacterial infection of the gut. These data expand the roles of T-regs to include tempering inflammation during acute infection in addition to the well-established roles of T-regs in chronic infection, control of immune homeostasis, and autoimmune disease.
Interleukin-17A during Local and SystemicStaphylococcus aureus-Induced Arthritis in Mice
Authors: Henningsson Louise , Jirholt Pernilla , Lindholm Catharina , Eneljung Tove , Silverpil Elin , Iwakura Yoichiro , Linden Anders , Gjertsson Inger 
Published: June 2010

ABSTRACTStaphylococcus aureusis one of the dominant pathogens that induce septic arthritis in immunocompromised hosts, e.g., patients suffering from rheumatoid arthritis treated with immunosuppressive drugs.S. aureus-induced arthritis leads to severe joint destruction and high mortality despite antibiotic treatment. Recently, interleukin-17A (IL-17A) has been discovered to be an important mediator of aseptic arthritis both in mice and humans, but its function inS. aureus-induced arthritis is largely unknown. Here, we investigated the role of IL-17A in host defense against arthritis following systemic and localS. aureusinfectionin vivo. IL-17A knockout mice and wild-type mice were inoculated systemically (intravenously) or locally (intra-articularly) withS. aureus. During systemic infection, IL-17A knockout mice lost significantly more weight than the wild-type mice did, but no differences were found in the mortality rate. The absence of IL-17A had no impact on clinical arthritis development but led to increased histopathological erosivity late during systemicS. aureusinfection. Bacterial clearance in kidneys was increased in IL-17A knockout mice compared to the level in wild-type mice only 1 day after bacterial inoculation. During systemicS. aureusinfection, serum IL-17F protein levels and mRNA levels in the lymph nodes were elevated in the IL-17A knockout mice compared to the level in wild-type mice. In contrast to systemic infection, the IL-17A knockout mice had increased synovitis and erosions and locally decreased clearance of bacteria 3 days after local bacterial inoculation. On the basis of these findings, we suggest that IL-17A is more important in local host defense than in systemic host defense againstS. aureus-induced arthritis.
Heterogeneity in Search Strategies among Cochrane Acupuncture Reviews: Is There Room for Improvement?
Authors: Lui Steve , Smith Erica J , Terplan Mishka 
Published: June 2010

Objective Given the international focus and rigorous literature searches employed in Cochrane systematic reviews, this study was undertaken to evaluate strategies employed in Cochrane reviews and protocols assessing acupuncture as a primary or secondary intervention. Methods The Cochrane Collaboration of systematic reviews was searched in February 2009 for all reviews and protocols including information on acupuncture. Information was abstracted from all retrieved articles on review status, type and number of English and Chinese language databases searched, participation of at least one Chinese speaking author and language restriction. Frequencies were calculated and bivariate analyses were performed stratifying on interventions of interest to assess differences in search strategy techniques, language restrictions and results. Results The search retrieved 68 titles, including 48 completed reviews, 17 protocols and three previously withdrawn titles. Acupuncture was the primary intervention of interest in 44/65 (67.7%) of the retrieved reviews and protocols. While all articles searched at least one English language database, only 26/65 (40.0%) articles searched Chinese language databases. Significantly more articles where acupuncture was the primary intervention of interest searched Chinese language databases (53% vs 9%, p<0.01). Inconclusive findings as to the effectiveness of acupuncture were found in 28/48 (58.3%) of all completed reviews; this type of finding was more common in reviews which did not search any Chinese language databases. Conclusions It is important for reviews assessing the effectiveness of acupuncture to search Chinese language databases. The Cochrane Collaboration should develop specific criteria for Chinese language search strategies to ensure the continued publication of high-quality reviews.
Allergic and non-allergic rhinitis in swimmers: clinical and cytological aspects
Authors: Gelardi Matteo , Ventura Maria Teresa , Fiorella Raffaele , Fiorella Maria Luisa , Russo Cosimo , Candreva Teresa , Carretta Antonella , Passalacqua Giovanni 
Published: June 2010

BackgroundRhinitis, either allergic or non-allergic, is frequent in athletes, particularly in swimmers. In this latter case, exposure to chlorine in swimming pools seems to play a relevant role, since it can exacerbate a pre-existing allergic rhinitis (AR) or produce a non-specific irritation. The aim of this study was to detail the clinical and cytological characteristics of rhinitis in swimmers, and to assess the possible role of chlorine-induced symptoms.MethodsElite swimmers with rhinitis symptoms underwent a complete diagnostic work-up, including allergy testing, nasal cytology and anterior rhinomanometry. Those evaluations were repeated after 1 month of use of a nasal clip during swimming. A matched group of asymptomatic swimmers was also studied. A total of 74 swimmers (54 symptomatic and 20 controls), with an age range of 9–21 years, were studied. In the control group, only mild and non-specific findings were observed, and only two had a positive skin test.ResultsIn the symptomatic group, 24 (44%) had AR, and 19 (35%) had a predominant neutrophilic inflammation. The use of a nose clip reduced cellular infiltration and nasal resistances only in the subjects with neutrophilic rhinitis, whereas a clinical improvement was seen also in AR.ConclusionA neutrophilic rhinitis occurs in a large proportion of swimmers. This seems to be irritative in its nature and can be prevented by avoiding the direct contact with chlorinated water.
A comparison of two treatment protocols in the management of exercise-associated postural hypotension: a randomised clinical trial
Authors: Anley Cameron , Noakes Timothy , Collins Malcolm , Schwellnus Martin P 
Published: June 2010

ObjectiveTo investigate which of two commonly used treatment protocols for exercise-associated postural hypotension (EAPH) resulted in earlier discharge from the medical facility.MethodsThis randomised clinical field trial was undertaken at two Ironman Triathlon competitions and one ultra-distance footrace. All collapsed athletes admitted to the medical facilities were considered for the trial. Following clinical assessment and special investigations to confirm the diagnosis of EAPH, 28 athletes were randomly assigned to an oral fluid and Trendelenburg position (OT=14) or an intravenous fluid (IV=14) treatment group. Following admission fluid intake was recorded, and all athletes were assessed clinically (blood pressure, heart rate, level of consciousness) every 15 min until discharge criteria were met. The main measure of outcome was the time to discharge (min).ResultsOn admission, subjects in the OT and IV groups were similar with respect to age, systolic blood pressure, heart rate and serum sodium concentration. There were no significant differences in heart rate, systolic and diastolic blood pressure between groups and over time until discharge. The fluid intake during the treatment period was significantly greater in the IV group (IV 1045±185 ml, OT 204±149 ml; p<0.001). The average time to discharge for the OT group (58±23 min) was similar to that of the IV group (52.5±18 min; p=0.47).ConclusionEndurance athletes with EAPH can be treated effectively using the Trendelenburg position and oral fluids and the administration of intravenous fluids does not reduce the time to discharge. The findings of this study support the hypothesis that EAPH is a result of venous pooling due to peripheral vasodilatation, rather than dehydration.
Acceptability of offering financial incentives to achieve medication adherence in patients with severe mental illness: a focus group study: Figure 1
Authors: Priebe Stefan , Sinclair Julia , Burton Alexandra , Marougka Stamatina , Larsen John , Firn Mike , Ashcroft Richard 
Published: June 2010

BackgroundOffering financial incentives to achieve medication adherence in patients with severe mental illness is controversial.AimsTo explore the views of different stakeholders on the ethical acceptability of the practice.MethodFocus group study consisting of 25 groups with different stakeholders.ResultsEleven themes dominated the discussions and fell into four categories: (1) ‘wider concerns’, including the value of medication, source of funding, how patients would use the money, and a presumed government agenda behind the idea; (2) ‘problems requiring clear policies’, comprising of practicalities and assurance that incentives are only one part of a tool kit; (3) ‘challenges for research and experience’, including effectiveness, the possibility of perverse incentives, and impact on the therapeutic relationship; (4) ‘inherent dilemmas’ around fairness and potential coercion.ConclusionsThe use of financial incentives is likely to raise similar concerns in most stakeholders, only some of which can be addressed by empirical research and clear policies.
The Second–Generation Global Forecast System at the Central Weather Bureau in Taiwan
Authors: Liou Chi–Sann , Chen Jen–Her , Terng Chuen–Teyr , Wang Feng–Ju , Fong Chin–Tzu , Rosmond Thomas E. , Kuo Hong–Chi , Shiao Chih–Hui , Cheng Ming–Dean 
Published: June 2010

Abstract
The global forecast system (GFS), which started its operation in 1988 at the Central Weather Bureau in Taiwan, has been upgraded to incorporate better numerical methods and more complete parameterization schemes. The second-generation GFS uses multivariate optimum interpolation analysis and incremental nonlinear normal-mode initialization to initialize the forecast model. The forecast model is a global primitive equation model with a resolution of 18 sigma levels in the vertical and 79 waves of triangular truncation in the horizontal. The forecast model includes a 1.5-order eddy mixing parameterization, a gravity wave drag parameterization, a shallow convection parameterization, a relaxed version of Arakawa–Schubert cumulus parameterization, grid-scale condensation calculation, and longwave and shortwave radiative transfer calculations with consideration of fractional clouds. The performance of the second-generation GFS is significantly better than the first-generation GFS. For two 3-month periods in winter 1995/96 and summer 1996, the second-generation GFS provided forecasters with 5-day forecasts where the averaged 500-mb height anomaly correlation coefficients for the Northern Hemisphere were greater than 0.6.
Observational data available to the GFS are much less than those at other numerical weather prediction centers, especially in the Tropics and Southern Hemisphere. The GRID messages of 5° resolution, ECMWF 24-h forecast 500-mb height and 850- and 200-mb wind fields available once a day on the Global Telecommunications System are used as supplemental observations to increase the data coverage for the GFS data assimilation. The supplemental data improve the GFS performance both in the analysis and forecast.
Health Insurance Status and Control of Diabetes and Coronary Artery Disease Risk Factors on Enrollment Into the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Grogan Mary , Jenkins Margaret , Sansing Veronica V. , MacGregor Joan , Mori Brooks Maria , Julien-Williams Patricia , Amendola Angela , Dawn Abbott J. ,   BARI 2D Study Group
Published: June 2010

Purpose The purpose of this study was to examine measures of chronic disease severity and treatment according to insurance status in a clinical trial setting. Methods Baseline insurance status of 776 patients with type 2 diabetes and stable coronary artery disease (CAD) enrolled in the United States in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was analyzed with regard to measures of metabolic and cardiovascular risk factor control. Results Compared with patients with private or public insurance, the uninsured were younger, more often female, and less often white non-Hispanic. Uninsured patients had the greatest burden of CAD. Patients with public insurance were treated with the greatest number of medications, had the greatest self-reported functional status, and the lowest mean glycosylated hemoglobin and low-density lipoprotein (LDL) cholesterol values. Overall, for 5 measured risk factor targets, the mean number above goal was 2.49 ± 1.18. After adjustment for demographic and clinical variables, insurance status was not associated with a difference in risk factor control. Conclusions In the BARI 2D trial, we did not observe a difference in baseline cardiovascular risk factor control according to insurance status. An important observation, however, was that risk factor control overall was suboptimal, which highlights the difficulty in treating type 2 diabetes and CAD irrespective of insurance status.
Making India’s Labour Markets Inclusive
Authors: Sabharwal Manish , Reddy Kavitha 
Published: June 2010

Growth is a necessary but not sufficient condition for poverty reduction. Reforming our education, employability and employment ecosystem is key to making progress. This article makes the case that India’s next wave of poverty reduction will come from accelerating India’s four labour market transitions; farm to non-farm, rural to urban, unorganised to organised and subsistence self-employment to decent wage employment. Not everybody agrees; people believe that urbanisation is a curse, farms provide a happy and contended existence, entrepreneurship is a solution to unemployment and the unorganised sector is a highly flexible response to India’s governance deficit. We disagree. We believe that the biggest lesson of India’s economic reforms is that growth is a necessary but not sufficient condition for poverty reduction. Poverty reduction needs access. Most Indians are unable to escape their financial, geographic or social opening balance (the Ovarian lottery) because our non-inclusive labour markets and human capital ecosystem do not provide access. Policy must accelerate these four labour market transitions because these are journeys to a better life for most Indians. Access is India’s unfinished agenda and the 3E focus (employment, employability and education) may be the most sustainable vehicles for creating access. Unfortunately, the global financial crisis is shifting the reform debate back to the dated fundamentalism around the private versus public sector. Reforms are about making our labour markets, economy and country more inclusive. They are about creating equality of opportunity and not equality of outcomes. They are about helping people escape their losing tickets in the Ovarian lottery.