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The number of international medical graduates (IMG) in radiology residencies has varied from year to year even as the number of candidates continues to grow. It is unclear from which countries the IMGs are arriving and what visas are being used to accommodate them. We sent a survey to 195 program directors (PD) in diagnostic radiology (DR) inquiring about the number and nationality of IMG residents in their program, their attitudes about IMG candidates, the performance of their IMG trainees, and the visas that are offered. We received responses from 121 of 195 (62.1%) DR programs (121/149 = 81.2% of actionable emails). 80/121 (66.1%) had at least one IMG in their DR residency program and the countries of origin included India (36), Iran (30), Saudi Arabia (24), Egypt (16), Canada (14), Brazil (14), and Pakistan (9), as the most common. While most programs (76/104, 73.1%) offered J1 visas, 23/99 (23.2%) provided H-1B visas to trainees. IMG DR residents overall performed as well as American graduates, with an equal number of PDs saying IMGs performed better and worse than American graduates. PDs' issues with IMGs centered on visas: (1) expense, (2) lack of familiarity, (3) Educational Commission for Foreign Medical Graduates regulations, and (4) time commitment in submitting paperwork. Most radiology IMG residents originate from India and Middle Eastern countries. Once enrolled, IMG residents perform similarly to US graduates. However, adding IMG candidates to the training program requires overcoming bureaucratic and monetary hurdles around visas. Most DR international medical graduate residents are from India or the Middle East. Although their performance is the same as American graduates in general, PDs note the monetary and bureaucratic hassles accompanying their recruitment. [ABSTRACT FROM AUTHOR]

Cardiology conferences represent a major avenue for learning, career advancement, and professional networking. Yet, costs of attending these conferences represent a major barrier, particularly for trainees and participants from low-middle-income countries (LMICs). Our study aimed to analyze the registration fees of major cardiology conferences worldwide. We included conferences organized by international cardiovascular societies and those representing global regions. We did not include individual national or institutional conferences due to inability to systematically identify them. We collected 2024 registration fees from official conference websites, taking 2023 or 2022 fees if unavailable, and categorized them according to career stage and society membership status. Where specified, we chose 'early-bird' fees. All fees were converted to US dollars according to currency exchange rates per the International Monetary Fund on December 4, 2023, or if unavailable, per the last reported US Treasury Data. Other data collected included host country, virtual option availability, and LMIC discounts. 30 (65.2 %) conferences provided discounts for medical students, regardless of membership status, while 1 (2.2 %) provided discounts only for student-members. 36 (78.2 %) conferences offered discounts for residents/fellows, while 2 (4.3 %) offered discounts only for resident/fellow-members. Median fees for students and residents/fellows with membership were $255 and $287 (in US dollars), respectively while median fees for non-members were $303.5 and $397, respectively. 31 (67.4 %) conferences provided discounts for staff- members. Median fees for staff were $701 and $800 for members and non-members, respectively. Only 12 (26.1 %) conferences mentioned a virtual component, with 11 offering discounted registration compared with in-person rates. 7 (15.2 %) conferences had special in-person fees for LMIC-based registrants. 5 offered the same discounted rate regardless of training stage, while 2 offered additional discounts for trainees. We found that conference registration costs were substantial, including for trainees, with only a minority of conferences providing discounted rates for LMICs. Professional societies must reduce registration costs, potentially by implementing a tiered system based on training stage and country of origin. Further, to augment LMIC participation, dedicated scholarships and mentorship programs for LMIC-based registrants are needed. [ABSTRACT FROM AUTHOR]

• VISA is essential in antiviral innate immunity. • DUT-M interacts with VISA and RIG-I. • DUT-M facilitate the assembly of VISA-TRAF2 complex and augment the polyubiquitination of TRAF2. • DUT-M impairs negatively regulates IRF3-induced IFNβ production upon viral stimulation. Upon recognition of intracytoplasmic viral RNA, activated RIG-I is recruited to the mitochondrion-located adaptor protein VISA (also known as MAVS, CARDIF, and IPS-1). VISA then acts as a central signaling platform for linking RIG-I and downstream signaling components, such as TRAF2, 5, and 6, TBK1, and IKK, leading to activation of the kinases TBK1 and IKK. These activated kinases further phosphorylate the transcription factors IRF3/7 and NF-κB, leading to the induction of downstream antiviral genes. Here, we report a mitochondrial isoform, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DUT-M, as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I to facilitate the assembly of the VISA-TRAF2 complex and to augment the polyubiquitination of TRAF2, leading to potentiated activation of IRF3 dimerization and phosphorylation of P65, and enhanced VISA-mediated innate immune response. RLR-VISA-mediated IRF3 dimerization and P65 phosphorylation, were inhibited in DUT-knockdown and DUT-deficient 293 cells. Thus, DUT-M is a positive regulator of the RIG-I-VISA-mediated innate immune response to RNA viruses. [ABSTRACT FROM AUTHOR]

International medical graduates (IMGs) are medical graduates who have received their degree from international medical schools. IMGs must undertake a 3-step process to apply to the National Residency Matching Program match. First, they must obtain a valid standard certificate from the Educational Commission for Foreign Medical Graduates. Following certification, they must apply for and secure a position in a residency training program. Third, they must obtain a visa that would enable them to commence their training. In this article, we delve thoroughly into these stepladders to provide IMGs with a clear roadmap of the process as well as contacts to key agencies that may provide more comprehensive assistance. [ABSTRACT FROM AUTHOR]

Objective Development of antimicrobial resistance during monotherapy of complicated methicillin-resistant Staphylococcus aureus bacteremia is problematic due to cross-resistance between vancomycin (VAN) and daptomycin, the only approved agents for this condition. Our objective was to demonstrate that development of resistance under conditions of suboptimal VAN (200 mg q 12 h) exposure in S. aureus can be attenuated by addition of cefazolin (CFZ). Methods Two strains of S. aureus , 1 methicillin-susceptible Staphylococcus aureus (MSSA) (RN9120) and 1 methicillin-resistant S. aureus (MRSA) (JH1), were evaluated. The organisms were exposed to subtherapeutic VAN concentrations in a 1-compartment pharmacokinetic/pharmacodynamic model combined with recycling in the presence and absence of CFZ. Changes in MIC to glyco/lipopeptides and β-lactams along with susceptibility to human cathelicidin LL-37 killing were studied. Population analysis profiles (PAPs) were performed to detect changes in VAN heteroresistance. Results VAN MIC of both organisms increased from 1 to 4 mg/L within 144 h under subtherapeutic VAN exposure. Increase in VAN MIC was associated with increased glyco/lipopeptides MICs. Additionally, increased survival in LL-37 killing assays from 40% to >90% accompanied the increase in VAN MIC. Addition of CFZ prevented the emergence of VAN-intermediate S. aureus . PAPs demonstrated an attenuation of VAN area under the curve shift (reduced organism selection with higher MICs values) when suboptimal VAN exposure was accompanied with CFZ compared to VAN alone (MSSA 17.81 versus 36.027, MRSA −0.35 versus 17.92, respectively). Given the emerging data on the clinical benefits of β-lactam adjunctive therapy in refractory MRSA bacteremia, additional studies on a larger collection of clinical isolates are needed to establish the utility of VAN plus CFZ for treatment of MRSA bacteremia. [ABSTRACT FROM AUTHOR]

Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp . A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S -octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram. [ABSTRACT FROM AUTHOR]

A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S -alkyl chains of 7–9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as antibiotic adjuvants in combination therapy of S. aureus infections with reduced vancomycin susceptibility. [ABSTRACT FROM AUTHOR]

The aim of the present study is to provide a picture for geopolitical globalization: the role of all world countries together with their contribution towards globalization is highlighted. In the context of the present study, every country owes its efficiency and therefore its contribution towards structuring the world by the position it holds in a complex global network. The location in which a country is positioned on the network is shown to provide a measure of its “contribution” and “importance”. As a matter of fact, the visa status conditions between countries reflect their contribution towards geopolitical globalization. Based on the visa status of all countries, community detection reveals the existence of 4 + 1 main communities. The community constituted by the developed countries has the highest clustering coefficient equal to 0.9. In contrast, the community constituted by the European eastern blocks plus some middle eastern countries has the lowest clustering coefficient, approximately equal to 0.65. PR China is the exceptional case. Thus, the picture of the globe issued in this study contributes towards understanding “how the world works”. [ABSTRACT FROM AUTHOR]

Résumé Introduction La construction d’une identité vocationnelle est au cœur du développement de l’adolescence à l’entrée dans l’âge adulte. Elle relève de six processus évalués dans un questionnaire auto-rapporté, le « Vocational Identity Status Assessment » (VISA) élaboré en langue anglaise (Porfeli et al., 2011). Objectif Le présent article a pour but la validation française du VISA à des fins à la fois de recherche et d’applications dans une démarche d’accompagnement individualisé d’adolescents scolarisés et de jeunes adultes poursuivant des études. Méthode L’étude empirique a porté sur un échantillon de 1655 adolescents et jeunes adultes scolarisés. Les processus identitaires ont été évalués grâce à trois questionnaires : le VISA, le DIDS et l’U-MICS. Résultats Les analyses statistiques réalisées ont permis d’analyser les qualités psychométriques du VISA et d’identifier six statuts d’identité vocationnelle définis dans la littérature. De plus, la présentation de deux profils individuels illustre les possibilités d’applications. Conclusion Le VISA est un questionnaire présentant de bonnes qualités psychométriques utiles dans l’identification des processus à l’œuvre dans la construction de l’identité vocationnelle. Introduction Vocational identity construction is a core developmental task from adolescence to emerging adulthood. It is based on six processes assessed by a self-report scale, the “Vocational Identity Status Assessment” (VISA) designed in English by Porfeli et al. (2011). Objective The aim of the current study was to validate a French version of the VISA both for research considerations and applications to help in adapting individual assistance and counseling to adolescent and emerging adult students. Method Participants were 1655 French adolescent and emerging adult students. The identity processes were assessed by three scales: the VISA, the DIDS and the U-MICS. Results The statistical analyses we performed allowed to test the psychometric properties of the VISA and to identify six vocational identity statuses previously defined in the literature. Moreover, the presentation of two individual profiles illustrated the opportunities for application. Conclusion The VISA is a self-report questionnaire with good psychometric properties, and useful for the identification of the processes involved in the vocational identity construction. [ABSTRACT FROM AUTHOR]

Reduced vancomycin susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) is a worldwide problem. Unfortunately, its genetic marker and molecular mechanisms remained unknown. This study investigated differential phenotypic characteristic and protein expression profiles among three groups of MRSA isolates, including vancomycin-susceptible S. aureus (VSSA), heterogeneous vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) ( n = 7 isolates/group). Phenotypic characteristic revealed significant greater number of isolates with non-spreading colony in VISA as compared to both VSSA and hVISA groups. 2-DE followed by nanoLC-MS/MS analyses revealed increased glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in both hVISA and VISA, whereas 50S ribosomal protein L14 (RplN) and DNA-binding protein II (Hup) were increased only in VISA. The non-spreading colony and GAPDH level of MRSA may be used as the markers for differentiation of VSSA, hVISA and VISA. [ABSTRACT FROM AUTHOR]

Résumé Objectifs Les tendinopathies patellaires et calcanéennes demeurent des affections musculosquelettiques très fréquentes chez les sportifs. Le but de notre travail était de valider une version française du Victorian Institute of Sports Assessment – Patellar et – Achilles (VISA-P et VISA-A), questionnaires en anglais développés respectivement afin d’évaluer la sévérité des tendinopathies patellaires et calcanéennes. Matériels et méthodes La traduction française et l’adaptation transculturelle du VISA-P et du VISA-A ont été réalisées selon les recommandations internationales. Pour ces adaptations, 92 (VISA-P) et 116 (VISA-A) sujets furent recrutés et répartis en 3 groupes (asymptomatiques, pathologiques et sportifs à risque), afin de tester ses propriétés psychométriques. Tous ces sujets durent également répondre au MOS SF-36 pour la validité de construit. Résultats La moyenne des scores du VISA-PF obtenu est de 99 pour le groupe sain, 53 pour le groupe pathologique et 86 pour le groupe à risque. La fidélité test-retest du VISA-PF est excellente avec un coefficient de corrélation intraclasse de 0,99, la cohérence interne mesurée par le coefficient α de Cronbach est très bonne (α = 0,9). Les corrélations entre le VISA-PF et les mesures divergentes du SF-36 sont faibles et les coefficients de corrélation mesurés entre les scores du VISA-PF et les items convergents du SF-36 ont des valeurs plus élevées. La moyenne des scores obtenus pour le VISA-AF est de 99 dans le groupe sain, 59 dans le groupe pathologique et 94 dans le groupe à risque. La fidélité test-retest du VISA-AF est excellente avec un coefficient de corrélation intraclasse de 0,99, la cohérence interne mesurée est très bonne (α = 0,92). Les corrélations entre le VISA-AF et certaines mesures divergentes du SF-36 sont faibles. Les coefficients de corrélation mesurés entre les scores du VISA-AF et les items convergents du SF-36 sont modérés. Aucun effet plancher ou plafond n’a été observé lors de l’évaluation des propriétés psychométriques des deux questionnaires. Conclusion Les versions françaises des questionnaires VISA-P et VISA-A constituent donc des adaptations françaises compréhensibles, fiables et adaptées aux patients francophones souffrant de tendinopathie patellaire ou calcanéenne. Summary Objectives Patellar and calcaneal tendinopathies remain very common musculoskeletal disorders in athletes. The Victorian Institute of Sports Assessment – Patellar and – Achilles (VISA-P and VISA-A), English questionnaires developed respectively to assess the severity of patellar and calcaneal tendinopathies. The purpose of our study was to validate a French version of these questionnaires. Materials and methods The French translation and intercultural adaptation of the VISA-P and the VISA-A are made according to international recommendations. For these adaptations, 92 (VISA-P) and 116 (VISA-A) subjects were recruited and divided into 3 groups (pathological, asymptotic and sporting risk), in order to test these psychometric properties. All these subjects also had to answer to the MOS SF-36 for the validity of construct. Results The mean VISA-PF scores were 99 for the healthy people, 53 for patients with patellar tendinopathy and 86 for the athletes. The VISA-PF shows excellent reliability with an inter-class correlation coefficient of 0.99. The internal consistency was 0.9 (Cronbach's alpha). The VISA-PF shows low correlations with the divergent sub-scales of the SF-36 and moderate correlations with the convergent sub-scales of the SF-36. The mean VISA-AF scores were 99 in the healthy group, 59 in the pathological group, and 94 in the group of athletes. The VISA-AF shows excellent reliability with an inter-class correlation coefficient of 0.99. The internal consistency was 0.92 (Cronbach's alpha). The VISA-AF shows low correlations with the divergent sub-scales of the SF-36 and moderate correlations with the convergent sub-scales of the SF-36. No floor and ceiling effects were detected during the evaluation of the two questionnaires. Conclusion The French versions of the VISA-P and VISA-A questionnaires are therefore French comprehensible adaptation, reliable and adapted to French-speaking patients suffering from patellar or calcaneal tendinopathies. [ABSTRACT FROM AUTHOR]

Baculovirus has been exploited for use as a novel vaccine vector. To investigate the feasibility and efficacy of recombinant baculoviruses (rBVs) expressing respiratory syncytial virus (RSV) fusion (F) proteins, four constructs (Bac-tF/64, Bac-CF, Bac-CF/tF64 and Bac-CF/tF64-VISA) were generated. Bac-tF64 displays the F ectodomain (tF) on the envelope of rBVs, whereas Bac-CF expresses full-length F protein in transduced mammalian cells. Bac-CF/tF64 not only displays tF on the envelope but also expresses F in cells. Bac-CF/tF64-VISA comprises Bac-CF/tF64 harboring the virus-induced signaling adaptor (VISA) gene. After administration to BALB/c mice, all four vectors elicited RSV neutralizing antibody (Ab), systemic Ab (IgG, IgG1, and IgG2a), and cytokine responses. Compared with Bac-tF64, mice inoculated with Bac-CF and Bac-CF/tF64 exhibited an increased mixed Th1/Th2 cytokine response, increased ratios of IgG2a/IgG1 antibody responses, and reduced immunopathology upon RSV challenge. Intriguingly, co-expression of VISA reduced Th2 cytokine (IL-4, IL-5, and IL-10) production induced by Bac-CF/tF64, thus relieving lung pathology upon a subsequent RSV challenge. Our results indicated that the Bac-CF/tF64 vector incorporated with the VISA molecule may provide an effective vaccine strategy for protection against RSV. [ABSTRACT FROM AUTHOR]

This paper examines how immigrants’ social capital affects their wealth holdings in the United States. I conceptualize visa sponsorship as a form of social capital and focus on three important factors – strength of ties, educational attainment, and race/ethnicity – that shape the relationship between immigrants’ social capital and wealth. I use the New Immigrant Survey and find that the relationship between visa sponsorship and wealth differs both by the strength of an immigrants’ tie to their network and their education. Notably, race/ethnicity only consistently stratifies the wealth of immigrants with employment sponsorship. Taken together, these results provide unique insight into immigrants’ economic integration in the United States and point to immigrants’ social capital as an important mechanism for wealth inequality. [ABSTRACT FROM AUTHOR]

Summary Background With the abuse of antibiotics, the methicillin-resistant Staphylococcus aureus (MRSA) strain became prevalent. Furthermore, Staphylococcus aureus with a character of vancomycin intermediate-resistance (VISA) has been found globally since the first report in Japan. The main objectives of this study were to report a case of VISA isolated from a Chinese patient who had never undergone Vancomycin treatment, and to determine its molecular character. Methods A total of 9 strains were recovered from a patient during the therapeutic process. Antimicrobial susceptibility testing was performed to determine their antibiotic susceptibility patterns. To detect the VISA strain's molecular epidemiological features, growth and morphological characters, we used multilocus sequence typing, autolysis assay and transmission electric microscope tests. Pulsed-field gel electrophoresis (PFGE) was performed to characterize the heterogeneities of all isolates. Results One isolate was found to exhibit vancomycin intermediated-resistant with MIC of 8 μg/ml. It was ST239-T030-agr-1, had thickened cell wall, and displayed a slower growth rate and reduced susceptibility to Triton X-100-induced autolysis than other strains. All 9 strains exhibited the same PFGE pattern. Conclusion This is the first report of VISA found in central China from a patient who had never received vancomycin treatment. [ABSTRACT FROM AUTHOR]

With the increasing emergence of antibiotic resistances old antibiotics became a valuable source to find agents suitable to address this problem. More than 20 years after the last report, our purpose was to re-evaluate the in vitro antibacterial activity of the topical agent primycin against current important bacterial pathogens. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of primycin were tested in comparison with agents widely applied topically, and with those of mupirocin and vancomycin, the topical and the non-topical gold-standard anti-MRSA agents. Primycin was ineffective (MIC > 64 μg/ml) against all the Gram-negative isolates tested. On the other hand, all the tested Gram-positive isolates were susceptible with MIC 90 values of 0.06 μg/ml for staphylococci and 0.5–1 μg/ml for enterococci, streptococci, and P. acnes isolates, including all the multiresistant strains. Against MRSA isolates primycin showed slightly higher activity than mupirocin, and inhibited the mupirocin-resistant strains also. MBC 90 values ranged from 0.25 to 2 μg/ml for the investigated Gram-positive species. The bactericidal effect proved to be concentration-dependent in time-kill experiments. Spontaneous resistant mutants did not emerge in single-step mutation experiments and the resistance development was very slow by serial passaging. Passaged S. aureus strains showing increased primycin MIC values exhibited elevated vancomycin and daptomycin MIC values also. Though elucidation of the mechanisms behind warrants further investigations, these correlations can be related to development of vancomycin-intermediate phenotype. From the point of view of medical practice it is noteworthy that the increased primycin MIC values remained far below the concentration accessible by local application of the agent. These data make primycin a remarkable object of further investigations as well as a promising candidate for topical application against multiresistant Gram-positive pathogens. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. Methods: All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. Findings: Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillinsusceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications: Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen. [ABSTRACT FROM AUTHOR]

Highlights: [•] We review current understanding VISA and hVISA genetics. [•] We review factors promoting evolution of VISA and loss of resistance phenotype. [•] We review virulence and other impacts of hVISA and VISA. [ABSTRACT FROM AUTHOR]

Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen that causes a wide range of both hospital- and community-acquired infections. The high prevalence of MRSA and the extensive use of vancomycin in Mainland China may lead to the emergence of vancomycin-intermediate S. aureus (VISA) isolates. In this case, we report a VISA isolate from a 34-year-old male patient with steam burn. The isolate was determined to be sequence type 239 staphylococcal cassette chromosome mec type III, the most prevalent MRSA clone in Mainland China. [Copyright &y& Elsevier]

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Abstract: By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu50. The mutants, occurring at an extremely low rate (<1×10−11/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated ‘reverse antibiotics’. [Copyright &y& Elsevier]

Abstract: A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC50) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds’ physicochemical properties. The 5-(4-OC4H9Ph, 5l), and 5-(4-CO2CH3Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC=1.95–1.25μg/mL) and T. cruzi (IC50 =7.91μM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH3Ph, 5e) derivative was the most active compound (MIC=3.28–2.95μg/mL). In this preliminary study, all synthesized 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested. [Copyright &y& Elsevier]

Abstract: This article estimates the effect of visa restrictions on bilateral trade flows and foreign direct investment (FDI) stocks. By raising the costs of travel and deterring some visitors, visa restrictions hamper personal contact across borders, which is detrimental to trade and FDI. Employing a standard gravity-type model in a global dyadic country sample, I estimate that if one country unilaterally requires a visa from nationals of the other country with no reciprocal restriction in place by the partner country, this lowers bilateral trade and FDI by up to 19 and 25 per cent, respectively. If both countries require a visa from nationals of the other country, the effect on trade is larger, but less than double, at up to 28 per cent, while the effect on FDI is essentially the same as for unilateral restrictions. With such substantial negative effects, it is at least questionable whether many of the existing visa restrictions would pass a cost-benefit test. [Copyright &y& Elsevier]

Abstract: As an adaptor molecule in the retinoic acid-inducible gene-I (RIG-I) signaling pathway, the virus-induced signaling adaptor (VISA) molecule activates NF-κB and IRF3 and thereby leads to the production of type I interferons (IFNs). To explore the potential of VISA as a genetic adjuvant for DNA vaccines, a eukaryotic expression plasmid, pVISA, was generated by cloning the VISA gene into the pVAX1vector. For comparison, the pTRIF plasmid was similarly constructed, encoding the known genetic adjuvant TRIF (TIR-domain-containing adapter-inducing interferon-β), an adapter in the Toll-like receptor (TLR) signaling pathway. Mice were immunized with the chimeric DNA vaccine pHA/NP147–155, which encodes the HA (hemagglutinin) fused with NP (nucleoprotein) CTL epitope (NP147–155) of H5N1 influenza virus, either alone or in combination with pVISA or pTRIF. Antigen-specific immune responses were examined in immunized mice. Our results demonstrate that co-immunization of the pHA/NP147–155 plasmid with the VISA adjuvant augmented DNA-raised cellular immune responses and provided protection against H5N1 influenza virus challenge in mice. In addition, our data suggest that VISA acts as a stronger adjuvant for DNA immunization than TRIF. We conclude that co-inoculation with a vector expressing the adaptor molecule VISA enhanced the protective immunity against H5N1 infection induced by pHA/NP147–155 and that VISA could be developed as a novel genetic adjuvant for DNA vaccines. [Copyright &y& Elsevier]

Abstract: Meticillin-resistant and vancomycin-intermediate Staphylococcus aureus (VISA) has emerged worldwide. However, clonal dissemination of VISA in hospitals has rarely been reported. We investigated 43 isolates of meticillin-resistant VISA [vancomycin minimum inhibitory concentrations (MICs) of 4μg/mL in 35 isolates and 8μg/mL in 8 isolates) recovered from 21 hospitalised patients. A glycopeptide was given prior to isolation of VISA in 14 of the patients. Five patients (23.8%) died despite vancomycin therapy. All isolates were inhibited by tigecycline at 0.5μg/mL, linezolid at 1μg/mL and ceftobiprole at 2μg/mL. Five isolates (11.6%) had reduced susceptibility to daptomycin (MICs of 1–2μg/mL). In addition, 6 of the 43 VISA isolates had decreased susceptibility to autolysis by 0.05% Triton X-100. All 43 VISA isolates carried staphylococcal chromosome cassette mec (SCCmec) type III and accessory gene regulator (agr) group I but none carried the Panton–Valentine leukocidin gene (lukS–lukF). None of the enterococcal van genes were detected in the 43 VISA isolates. Molecular typing generated by pulsed-field gel electrophoresis revealed that all isolates belonged to one pulsotype, indicating clonal dissemination of VISA isolates in the hospital. The high rate of non-susceptibility to daptomycin amongst these VISA isolates is alarming and indicates the limitation of this agent for the treatment of infections due to VISA. [ABSTRACT FROM AUTHOR]

Vancomycin resistance in Staphylococcus aureus has emerged over the last ten years due to varying mechanisms and giving variable levels of resistance to vancomycin. The most resistant strains (fortunately rare) bear the vanA gene cluster and these are generally recognisable as MICs of vancomycin are usually found to be in the range 32-64mg/L. It should be noted that some automated systems have failed to detect these isolates. The much more commonly encountered GISA and hGISA vancomycin resistant strains of MRSA and methicillin sensitive Staph. aureus (MSSA) exhibit lower levels of resistance and difficulty is encountered in reliably defining and identifying these strains in clinical laboratories. No single completely reliable, convenient test either phonotypical genetic currently exists which can be readily applied in the clinical laboratory for the detection of hGISA/GISA. The population analysis profile (PAP) method is currently regarded as the reference method but is slow and tedious to perform on a large number of isolates. This enables the differentiation of hGISA and GISA from fully vancomycin sensitive strains. In the clinical laboratory the use of Meuller-Hinton agar with 5mg/L teicoplanin and a 10μL innoculum of MacFarland 0.5 incubated for 48h represents the most reliable and economical screening test. Further confirmation would be required using either macrodilution Etest methodology using an MIC ≥ 8mg/L of vancomycin and/or teicoplanin as the cut off for hGISA or the newer GRD (glycopeptide resistance detection) strip. [ABSTRACT FROM AUTHOR]

Abstract: The striking difference in evolution of type I IFN genes of fish and mammals poses the question of whether these genes are induced through similar or different signalling pathways in the two vertebrate groups. Previous work has shown that expression of both Atlantic salmon (Salmo salar) IFNa1 and mammalian IFN-β genes is dependent on IRF and NF-κB elements in their promoters. In mammals, IFN-β transcription is induced through the RIG-I/MDA5 pathway where the adaptor protein IPS-1 plays a key role in the signal transduction. In this work we show that an Atlantic salmon homologue of IPS-1 (AsIPS-1) mediates activation of the salmon IFNa1 promoter and an NF-κB driven promoter. AsIPS-1 shares only 18% identity in amino acid sequence with human IPS-1, but possesses the CARD, proline-rich and transmembrane domains found in mammalian IPS-1. Overexpression of AsIPS-1 resulted in induction of an antiviral state in the cells apparently due to induction of IFN. Deletion of the CARD and transmembrane domains of AsIPS-1 abolished its ability to activate the IFNa1 promoter and the NF-κB driven promoter, and thus its ability to induce an antiviral state. AsIPS-1 is located to mitochondria similar to human IPS-1. Taken together, IPS-1 plays a key role in the induction of Atlantic salmon IFNa1, which appears to be the first and major IFN induced in host cells upon recognition of viral dsRNA. [Copyright &y& Elsevier]

Abstract: It is known that multiple genome-wide transcriptional changes often accompany the development of antimicrobial resistance and occur in response to challenge with antimicrobial agents. We now show that inactivation of the staphylococcal accessory gene regulator sarA, which controls at least tens of genes in Staphylococcus aureus, leads to dramatic reductions in vancomycin and ciprofloxacin resistance in vancomycin-intermediate and ciprofloxacin-resistant strains of S. aureus. This is particularly evident when judged by antimicrobial-gradient plate analysis or population analysis profiles. Whilst the intact sarA cistron is required for full vancomycin resistance expression by vancomycin-intermediate S. aureus (VISA), sarA expression as determined by quantitative real-time polymerase chain reaction was found to be VISA strain-dependent. Reductions in vancomycin resistance expression levels following sarA inactivation do not necessarily include an alteration in autolysis. Expression of sarR, the negative regulator of sarA, was downregulated in two VISA mutants, and transcription of the alternative sigma factor sigB was downregulated in one VISA strain. This study contributes to a growing body of evidence demonstrating the importance of loci previously identified to control virulence in the regulation of clinically relevant antibiotic resistance mechanisms. [Copyright &y& Elsevier]

Abstract: Viral infection stimulates multiple signalling pathways in the innate immune system, leading to type 1 interferon production. Recent research has identified the mitochondrial protein MAVS as a key component of one intracellular pathway, definitively linking mitochondria to the mammalian antiviral defence system for the first time. [Copyright &y& Elsevier]

Abstract: Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N′-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF3 substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6–13.1μg/mL, and a Clog P value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates. [Copyright &y& Elsevier]

Abstract: Glycopeptides are among the most widely used agents for the treatment of serious infections caused by Gram-positive bacteria, with vancomycin recommended for the treatment of infections caused by β-lactam-resistant Staphylococcus aureus (MRSA). However, the utility of glycopeptides against MRSA has come into question owing to their poor tissue penetration, slow bactericidal activity and the emergence of strains with reduced susceptibility. A number of single-centre studies have demonstrated incremental increases in glycopeptide MICs for S. aureus strains over time – a phenomenon known as glycopeptide creep. High MICs have long been known to correlate with poorer clinical outcomes, but recent studies have shown that even small increases in MIC below the susceptibility breakpoint can affect the clinical efficacy of glycopeptides. The accurate measurement and ongoing surveillance of glycopeptide MICs at individual sites is therefore recommended to assist clinicians in their choice of empiric therapy for suspected serious S. aureus infections. [Copyright &y& Elsevier]

Abstract: The glycopeptide antibiotic vancomycin acts by binding to the D-alanyl-D-alanine terminus of the cell wall precursor lipid II in the cytoplasmic membrane. The purpose of this study was the identification of genes that might be involved in the vancomycin resistance mechanism. To this end, the expression profiles of two vancomycin intermediately resistant Staphylococcus aureus (VISA) strains, the clinical isolate S. aureus SA137/93A (Etest: 8μg/ml) and its laboratory mutant S. aureus SA137/93G (Etest: 12μg/ml) were analyzed using an S. aureus full-genome chip. The results indicated that an essential two-component regulatory system, yycF (vicR) and yycG (vicK) was drastically up-regulated in strain SA137/93A. Sequencing of the yycFG promoter region of strain SA137/93A revealed an insertion of IS256 in the predicted promoter region creating a potentially stronger hybrid promoter. In strain SA137/93G, IS256 was not integrated in the yycFG promoter region but, in previous studies, a copy of IS256 had been found to inactivate the tcaA gene (Maki et al. Antimicrob. Agents and Chemother. 48, 1953–1959 (2004)). Detailed population analyses showed that, in addition to the loss of SCCmec, the inactivation of tcaA seems to cause at least part of the increase in teicoplanin and vancomycin resistance in strain SA137/93G. [Copyright &y& Elsevier]

Abstract: Virus-induced signaling adaptor (VISA) is essential for host innate immune responses against double-stranded RNA viral infection and viral replication. It is an adaptor that activates the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) that regulate the expression of type I interferons. The localization of VISA to the outer membrane of mitochondria and the cellular consequences of its activation implicate this protein in the cellular etiology of neurodegenerative disorders. [Copyright &y& Elsevier]

Abstract: Vancomycin has been the drug of choice for 30 years for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Emergence of decreased vancomycin susceptibility in MRSA strains presents a significant clinical problem with few therapeutic options. This study was performed to generate and characterise S. aureus strains with reduced susceptibility to vancomycin. Eighteen S. aureus strains were subjected to serial passaging on vancomycin to generate vancomycin intermediate resistant S. aureus (VISA) strains. Minimum inhibitory concentration (MIC) determination was performed for the parent and the passaged cultures with 13 different antibiotics. The strains were tested by the following five methods: simplified population analysis; CDC method; modified vancomycin agar screen; population analysis profile (PAP); and modified population analysis (PAP–area under the curve (AUC) ratio). Phenotypic changes such as doubling time, synergy with β-lactam antibiotics and effect on norA efflux pumps were also studied for these strains. The result indicated that 8 VISA mutants (vancomycin MICs, 8–16μg/mL) were generated in vitro from the 18 S. aureus strains. The CDC and modified agar methods proved to be the most sensitive and specific methods for detection of VISA strains. The PAP for all the VISA strains ranged from 12μg/mL to >16μg/mL, with a PAP–AUC ratio of >1.3. All mutants showed increased doubling time compared with their parent isolate. Synergism of the vancomycin and β-lactam combinations was observed for all methicillin-resistant mutants. Upon acquisition of vancomycin resistance, a few mutants showed decreased oxacillin resistance. Two VISA strains were chosen for molecular characterisation of the mecA gene and one mutant showed genotypic changes with deletion of mecA. Loss of norA efflux pumps leading to fluoroquinolone sensitivity was also observed in four mutants. [Copyright &y& Elsevier]

This paper describes an integration of recent new developments in snow, runoff and vegetation growth into the National Center for Atmospheric Research Land Surface Model (NCAR LSM). The new model, referred to as the Versatile Integrator of Surface and Atmosphere processes (VISA), has been validated with observed data. The results have demonstrated that the NCAR LSM, after integrating with these new developments, produces improved simulations of snow and runoff over the baseline version, and has an added capability to simulate the dynamics of leaf area index (LAI). Moreover, VISA, through its integration of new schemes, is not only important for studying land–atmosphere interactions in its own right, but also useful for helping interpret results from a parallel modeling activity—the Community Land Model (CLM) project. [Copyright &y& Elsevier]

We report a case of infective endocarditis due to vancomycin-intermediate Staphylococcus aureus (VISA) that did not respond to high doses of vancomycin. Initial vancomycin MIC of the last isolate recovered from blood was 8 μg/mL, but could be induced up to 32 μg/mL by consecutive growing with vancomycin. Clinical response was only accomplished when linezolid was included in therapy. [Copyright &y& Elsevier]

The emergence of vancomycin intermediate resistant Staphylococcus aureus (VISA) isolates in Japan, USA, France, Hong Kong and Korea among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, is of great concern. Vancomycin has been the drug of choice for the treatment of multiresistant MRSA infections in the last three decades, but the management of invasive MRSA infections will become a serious problem if VISA strains become widespread. VISA isolates reported to date have a vancomycin MIC of 8 mg/L, and were isolated from patients with underlying diseases whose long-term vancomycin treatment apparently failed. Since many VISA isolates also have been resistant to teicoplanin, the term glycopeptide-intermediate S. aureus (GISA) is more appropriate. The frequency of GISA isolates appears to be extremely low; to date, only 10 GISA infections have been reported worldwide. However, heterogeneous resistance to glycopeptides (h-GISA) have been reported in Japan, Europe and Thailand. These h-GISA strains showed vancomycin MICs ranging from 1 to 4 mg/L, but had subpopulations that could grow on agar plates containing 4–8 mg/L, which may represent the first step in the development of GISA strains. Although GISA isolates have shown resistance to many antimicrobials, all GISA isolates remain susceptible to co-trimoxazole and some of them to other common antimicrobials. Currently, there are no recommended therapy guidelines for GISA infections, although in recent studies, several new drugs have shown promising activity against GISA strains. In addition, synergy between glycopeptides and β-lactams against GISA strains was observed in some in vivo and in vitro studies. Specific MRSA/GISA control programs, rational antibiotic policies, including the reduction of glycopeptide use, and rapid laboratory detection of GISA and h-GISA strains are the key measures in preventing the spread of these strains. [ABSTRACT FROM AUTHOR]

Dalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5–16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA. We simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (f Cmax 9.9 μg/mL, β-elimination t 1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities. Dalbavancin was bactericidal against most strains for days 1–4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64–128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4–16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin–β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR , apt , stp1 , and atl. In our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR -associated genes. [ABSTRACT FROM AUTHOR]

Abstract: A vancomycin-intermediate Staphylococcus aureus (VISA) isolated from the blood of a 46-year-old patient with endocarditis was determined to be pulsed-field type USA300, daptomycin nonsusceptible, and positive for the Panton–Valentine leukocidin genes. Development of the VISA phenotype does not appear limited to traditional health care strains of S. aureus. [Copyright &y& Elsevier]

The aim of the present study was to investigate the prevalence of vancomycin resistance in clinical methicillin resistant Staphylococcus aureus (MRSA) isolates in our hospital by screening on Mueller–Hinton agar with 5 mg/l teicoplanin (MH-Teico), as recommended by the Comité de l’Antibiogramme of the Société Française de Microbiologie (CA-SFM). Seventeen of 1002 clinical MRSA isolated from 404 patients showed in 2003 growth of at least four colonies on this medium, but only one was confirmed as homogeneous vancomycin-resistant S. aureus (VISA) and five as heterogeneous VISA (hVISA) by population analysis. None of the patients presented with severe infection but awareness is needed and screening on MH-Teico as recommended by CA-SFM is a convenient method. Surveillance should be focused on patients with risk factors for selection of such strains: patients with a prolonged course of glycopeptide therapy and persistence of MRSA infection or colonization. [Copyright &y& Elsevier]

We analyzed sequences of gra SR, vraS R, wal KR and rpo B genes in hVISA from Brazil. Five isolates showed mutations in at least one gene. rpo B H481N and gra S T224I were the most frequent mutations, followed by gra R D148Q and wal K A468T. Our study reinforces the heterogeneity of genetic patterns among hVISA. • Comparative evaluation of the role of mutations in four target genes (gra SR, vra SR, wal KR and rpo B) and their impact on decreased susceptibility to vancomycin. • The impact on the phenotype expression was evaluated through the population profile analysis tests – area under the curve (before and after induction), induction of resistance, minimal bactericidal concentration, vancomycin tolerance and slow VISA phenotype. • Mutations in wal KR and vra SR, alone, did not demonstrate relevance. Although mutations in gra SR have shown the greatest impact on decreased susceptibility, the sum of the performance of other genes may also lead to the development of the hVISA phenotype. • Because of the multiplicity of genes involved, it is difficult to establish a single molecular marker as a predictor of resistance. Phenotypic screening tests (MIC, PAP-AUC) are still the best indicators of therapeutic failure and should be taken into account in the clinical decision to maintain or change vancomycin therapy. [ABSTRACT FROM AUTHOR]

Résumé Du remède secret à la spécialité pharmaceutique, les exigences concernant le médicament se sont accrues au fil du temps dans le but de garantir aux patients une sécurité d’utilisation maximale. La procédure d’autorisation de mise sur le marché fixe dorénavant les conditions et précautions d’emploi de toute spécialité disponible. Summary From secret remedies to proprietary medicines, regulations concerning drugs have increased over time in order to guarantee patients maximum safety. The marketing authorisation procedure now stipulates the conditions and precautions of use of all available medicines. [ABSTRACT FROM AUTHOR]

Abstract: We report a case of infective endocarditis due to vancomycin-intermediate Staphylococcus aureus (VISA). This was treated with a combination of intravenous linezolid and fusidic acid. Cure was achieved without surgical intervention. [ABSTRACT FROM AUTHOR]