Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study).

Background: Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods: We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) algorithm. Results: Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions: Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients.

Impact of specific modes of circumferential resection margin involvement in rectal cancer local recurrence: A retrospective study.

PURPOSE: To compare the local recurrence rate and overall survival between patients with circumferential resection margin (CRM) involvement by direct tumor spread and by a tumor within a lymph node. METHODS: A total of 776 patients diagnosed with rectal cancer underwent rectal resection. Patients with CRM involvement by direct tumor spread were named group A. CRM involvement by tumor within a lymph node formed group B. Patient data, including sex, age, pT, pN, stage I-III versus IV, neoadjuvant radiotherapy, adjuvant chemotherapy, carcinoembryonic antigen, primary tumor location, lymph node retrieval, and need for abdominoperineal resection, were compared between both groups. RESULTS: In total, 10.5% of the patients had CRM involvement. Of these, in 57 cases (7.3%), it was by direct tumor spread and in 19 cases (2.4%) by tumor within a lymph node. Other types of CRM involvement were found in six patients. With a mean follow-up of 32.9 months, 18 patients from group A (31.5%) and one patient from group B (5.2%) suffered a local recurrence. Local recurrence-free survival was significantly higher in patients from group B (P = 0.049). Patients in stage I-III (P = 0.037) and from group B ( P = 0.049) had better overall survival. CONCLUSION: Patients with CRM involvement by tumor within a lymph node have a low risk of local recurrence and better overall survival than patients with CRM involvement by direct tumor spread.

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study.

Background: Surveillance of HIV-1 resistance in treated patients with a detectable viral load (VL) is important to monitor, in order to assess the risk of spread of resistant viruses and to determine the proportion of patients who need new antiretroviral drugs with minimal cross-resistance. Methods: The HIV-1 protease and reverse transcriptase (RT) and integrase genes were sequenced in plasma samples from 782 consecutive patients on failing antiretroviral regimens, seen in 37 specialized centres in 2014. The genotyping results were interpreted using the ANRS v24 algorithm. Prevalence rates were compared with those obtained during a similar survey conducted in 2009. Results: The protease and RT sequences were obtained in 566 patients, and the integrase sequence in 382 patients. Sequencing was successful in 60%, 78%, 78% and 87% of patients with VLs of 51-200, 201-500, 501-1000 and >1000 copies/mL, respectively. Resistance to at least one antiretroviral drug was detected in 56.3% of samples. Respectively, 3.9%, 8.7%, 1.5% and 3.4% of patients harboured viruses that were resistant to any NRTI, NNRTI, PI and integrase inhibitor (INI). Resistance rates were lower in 2014 than in 2009. Resistance was detected in 48.5% of samples from patients with a VL between 51 and 200 copies/mL. Conclusion: In France in 2014, 90.0% of patients in AIDS care centres were receiving antiretroviral drugs and 12.0% of them had VLs >50 copies/mL. Therefore, this study suggests that 6.7% of treated patients in France might transmit resistant strains. Resistance testing may be warranted in all treated patients with VL > 50 copies/mL.

Spanish-language cognitive screening tests: a critical review.

INTRODUCTION: Dementia is a chronic, degenerative disease with a strong impact on families and health systems. The instruments currently in use for measuring cognitive impairment have different psychometric characteristics in terms of application time, cut-off point, reliability, and validity. The objective of this review is to describe the characteristics of the validated, Spanish-language versions of the Mini-Cog, Clock-Drawing Test, and Mini-Mental State Examination scales for cognitive impairment screening. DEVELOPMENT: We performed a three-stage literature search of articles published on Medline since 1953. We selected articles on validated, Spanish-language versions of the scales that included data on reliability, validity, sensitivity, and specificity. CONCLUSIONS: The 3 screening tools assessed in this article provide support for primary care professionals. Timely identification of mild cognitive impairment and dementia is crucial for the prognosis of these patients.

Performance of genotypic algorithms for predicting tropism for HIV-1 CRF01_AE recombinant.

OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations. RESULTS: Overall, 72.5%, 59.4%, 86.0%, 90.8% of the 207 HIV-1 CRF01_AE were R5-tropic viruses determined by Geno2pheno FPR5%, Geno2pheno FPR10%, the combined criteria and the 11/25 rule, respectively. A concordance of 82.6% was observed between Geno2pheno FPR5% and the combined criteria for CRF01_AE. The results were nearly similar for the comparison between Geno2pheno FPR5% and the 11/25 rule. More mismatches were observed when Geno2pheno was used with the FPR10%. Neither HIV viral load, nor current or nadir CD4 was associated with the discordance rate between the different algorithms. CONCLUSION: Geno2pheno predicted more X4-tropic viruses for this set of CRF01_AE sequences than the combined criteria or the 11/25 rule alone. For a conservative approach, Geno2pheno FPR5% seems to be a good compromise to predict CRF01_AE tropism.

Spanish-language screening scales: A critical review. / Escalas de tamizaje cognitivo en habla hispana: una revisión crítica.

INTRODUCTION: Dementia is a chronic, degenerative disease with a strong impact on families and health systems. The instruments currently in use for measuring cognitive impairment have different psychometric characteristics in terms of application time, cut-off point, reliability, and validity. The objective of this review is to describe the characteristics of the validated, Spanish-language versions of the Mini-Cog, Clock-Drawing Test, and Mini-Mental State Examination scales for cognitive impairment screening. DEVELOPMENT: We performed a three-stage literature search of articles published on Medline since 1953. We selected articles on validated, Spanish-language versions of the scales that included data on reliability, validity, sensitivity, and specificity. CONCLUSIONS: The 3 screening tools assessed in this article provide support for primary care professionals. Timely identification of mild cognitive impairment and dementia is crucial for the prognosis of these patients.

Multicenter evaluation of the NucliSens EasyQ HIV-1 v1.1 assay for the quantitative detection of HIV-1 RNA in plasma.

The Nuclisens EasyQ HIV-1 v1.1 assay (Biomerieux) is a real-time detection method combined with NASBA technology designed to measure plasma HIV-RNA. Its performance was assessed in 1008 clinical specimens collected from individuals infected with clade B (774) and non-B (234) HIV-1 variants at four European laboratories. The results were compared with those obtained using three other commercial viral load assays: Cobas Amplicor Monitor HIV-1 v1.5 (Roche), Versant HIV-1 RNA assay (Bayer) and Nuclisens HIV-1 QT (Biomerieux). Overall, the linearity, specificity and reproducibility of the EasyQ assay was comparable with that from the other tests. The correlation coefficient (R) between methodologies was 0.85 for Amplicor; 0.87 for Versant; and 0.91 for Nuclisens. The specificity of the assay was 99.4%. Of note, Versant missed 17% of specimens with non-B subtypes which could be detected by EasyQ, while Amplicor provided similar results than EasyQ. HIV-1 group O specimens were only detected by the EasyQ assay. In conclusion, the performance of the EasyQ assay seems to be similar to that of other HIV-1 viral load tests currently on the market, but it is more sensitive than Versant for HIV-1 non-B subtypes and shows a wider dynamic range than Amplicor. Moreover, as it incorporates the advantage of real-time detection procedures, it facilitates high throughput and short turnaround time.

Emergence of zidovudine and multidrug-resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy. STADI Group.

OBJECTIVE: Assessment of genotypic changes in the reverse transcriptase gene of HIV-1 occurring in antiretroviral naive patients treated by stavudine plus didanosine combination therapy. METHODS: Sequence analysis (codons 1-230) was performed after amplification of the reverse transcriptase gene from plasma samples collected at baseline and at the end of treatment from 39 previously treatment-naive patients treated for 24-48 weeks. RESULTS: At baseline, mutations associated with zidovudine resistance were detected in plasma from two patients: Asp67Asn/Lys219Gln and Leu210Trp. Among the 39 subjects, 18 (46%) developed mutations: one developed the Val75Thr/Ala mutation, four (10%) developed a Gln151Met multidrug-resistance mutation (MDR), associated in one of them with the Phe77Leu and the Phe116Tyr MDR mutations and 14 (36%) developed one or more zidovudine-specific mutations (Met41Leu, Asp67Asn, Lys70Arg, Leu210Trp, Thr215Tyr/Phe). The development of a Met41Leu zidovudine-specific mutation was associated with the development of a Gln151Met mutation in one patient. Other reverse transcriptase mutations known to confer resistance to nucleoside analogues were not detected. At inclusion, there was no statistical difference in HIV-1 load between patients who developed resistance mutations and those who did not. RNA HIV-1 load decrease was higher (P = 0.05) in patients who maintained a wild-type reverse transcriptase genotype (-2.22 log10 copies/ml) than in patients who developed resistance mutations (-1.14 log10 copies/ml). CONCLUSION: Stavudine/didanosine combination therapy is associated with emergence of zidovudine-related resistance or MDR mutations in naive patients. These findings should be considered when optimizing salvage therapy for patients who have received a treatment including stavudine/didanosine combination.

Susceptibility of several species of Candida and Torulopsis to fluconazole and ketoconazole.

The authors compared the in vitro antifungal activity of fluconazole, a new triazole antifungal agent, and ketoconazole, an imidazole derivative. The MIC values were determined against 50 strains of Candida albicans, 10 strains of C. guilliermondii, 10 strains of C. krusei, 10 strains of C. parapsilosis, 10 strains of C. pseudotropicalis, 10 strains of C. tropicalis and 15 strains of Torulopsis glabrata. The fungistatic activity was evaluated by the agar dilution method using BHI and casitone media after incubation for 48 h at 28-30 degrees C. Both antifungal agents showed higher activity when tested on casitone medium; however, the G-MIC values for ketoconazole were lower than those for fluconazole.

[Distribution, abundance and population parameters of Diapterus rhombeus (Pisces: Gerreidae) in Laguna de Términos, Campeche, Mexico]. / Distribución, abundancia y parámetros poblacionales de la mojarra Diapterus rhombeus (Pisces: Gerreidae) en la Laguna de Términos, Campeche, México.

Diapterus rhombeus dominates the nektonic community of Terminos Lagoon and is associated to zones with submerged vegetation, temperatures between 27 and 33 degrees C and salinity between 25 and 36.5 UPS. A total of 3,024 individuals were collected with a trawl net in 23 sites between September 1997 and September 1998. The length-weight model parameters are a = 0.0098; b = 3.155 with a 96% correlation. The growth parameters are L infinity = 20.4 cm, k = 0.74 and t(o) = -4.207 and the total mortality coefficient is 3.526. Fish length is 2.5-18.0 cm with a mode of 7.5 cm. Recruitment is continuous with a peak from May to August. The species uses several habitats of the lagoon mainly for feeding and growth, reproduction probably occurs in the adjacent continental shelf. Movements between continental shelf and the estuarine system represent a continuous energy flow.

[Comparative bioavailability and pharmacokinetics of Dolotren retard and Dolotren]. / Biodisponibilidad y farmacocinética comparadas de Dolotrén Retard frente a Dolotrén.

A randomized crossover study was designed in order to evaluate the bioequivalence of a sustained-release preparation (DR) of diclofenac sodium (Dolotrén RETARD) with respect to an enteric coated (D) tablet (Dolotren). For this purpose the bioavailability of both formulations, orally administered in single and multiple doses, was determined. Nine healthy volunteers were included in this study, receiving 100 mg of D and 100 mg of DR, firstly in single dose and then for 15 days b.i.d. for D group and once a day for DR group. For the analytical determination of diclofenac, blood samples at established time intervals, the day of the single dose and the 3rd, 7th and 15th day of multiple dose administration, were taken. The following kinetic parameters were determined: Cmac, tmax, alpha and beta, clearance, ka, area under the curve and absolute and relative bioavailability. When administered both endovenous and orally, the great interindividual variability in the kinetic characteristics of diclofenac sodium is evidenced. The lag time (tlag) for DR is 0.4 h, shorter than for D (2.2 h), which indicates a faster absorption in the upper sections of the gastrointestinal tract. Also tmax was shorter for Dr (1.9 h) than for D (4.3 h). Cmax obtained with D was higher tan with DR. The diclofenac sodium elimination process from plasma is significantly slower with DR than with D (t1/2 beta = 18.1 h and 2.5 h, respectively). In consequence, quantifiable plasmatic levels are maintained for at least 24 hours after administration of DR, but not of D. Absolute bioavailability of both preparations is about 80%, with great interindividual variations. Significant differences between the two preparations could not be demonstrated. Relative bioavailability between DR and D was 91.5%. None of the preparations when administered in repeated doses, D every 12 hours and DR every 24 hours, produced accumulation, neither their pharmacokinetic characteristics changed. Clinical and biological tolerance of both preparations were excellent, at doses used and for the period of time studied. Dolotren Retard is absorbed orally faster than Dolotren and maintains plasmatic levels longer, which allows it to be administered once a day, with a lesser incidence of undesirable effects related to Cmax.

Características clínicas y demográficas de pacientes oncológicos del Hospital Base Valdivia con complicaciones infecciosas. Enero-Julio 2013 / Clinical and demographic description of Oncological Patients with ongoing infectious complications in Hospital Base Valdivia. January - July 2013

El cáncer constituye la segunda causa de muerte en Chile y las infecciones constituyen uno de los principales gatillantes del deceso. El objetivo principal de esta investigación es describir las características clínicas y demográficas de los pacientes oncológicos del Hospital Base Valdivia (HBV) que presentaron complicaciones infecciosas entre el periodo enero-julio de 2013. Materiales y métodos: Se realizó un estudio de serie de casos que incluyó a todos los pacientes oncológicos hospitalizados que presentaron complicaciones infecciosas entre enero-julio de 2013, excluyendo a quienes rechazaran el consentimiento informado o tuvieran fichas clínicas incompletas. Se aplicaron instrumentos para determinar estado nutricional y nivel socioeconómico. Análisis computacional con estadística descriptiva. Resultados: Se pesquisaron 38 pacientes con un total de 52 infecciones. Dieciséis eran hombres y 22 mujeres, edad promedio 59 años. La mayoría pertenecía a estratos socioeconómicos bajos y poseía estudios básicos. Las neoplasias subyacentes más frecuentes fueron el cáncer de mama y cervicouterino. Dieciséis pacientes se encontraban en etapa IV y cerca de 2/3 estaban desnutridos. De las 52 infecciones 31 fueron localizadas, mientras 21 tuvieron respuesta sistémica, 2 pacientes fallecieron debido a la infección. Los sitios más frecuentes de afección fueron: árbol bronquial, tracto genitourinario y cavidad oral. Clínicamente se determinó que 44 de los cuadros fueron bacterianos, 3 fúngicos, 3 virales y 2 combinados. Discusión: Llama la atención el predominio de pacientes provenientes de niveles socioeconómicos y educacionales bajos. Si bien las infecciones pueden corresponder a cuadros potencialmente fatales en pacientes oncológicos, la mayoría de nuestros casos correspondieron a cuadros leves.

Cancer is the second leading cause of death in Chile and infections are one of the main-triggering of death. The main objective of this research is to describe clinical and demographic characteristics of oncological patients of Hospital Base Valdivia with ongoing infectious complications between January-July 2013. Material and methods: series of cases, we reviewed the medical records of all oncological patients who had infectious complications between January-July 2013, excluding those who rejected the invitation or had incomplete medical records. Also, tools for determining nutritional status and socioeconomic status were applied. Data went through computational analysis with determination of descriptive statistics. Result: 38 patients were included with total of 52 infections. Sixteen were men and 22 women, average age was 59 years. Most belonged to lower socioeconomic strata and only had basic education. The most common underlying neoplasms were breast and cervical cancer. Sixteen patients were in stage IV and about two-thirds were malnourished. 31 of the 52 infections were localized, while in 21 there was systemic response, 5 progressed to sepsis and 2 to septic shock, 2 patients died because of their infections. The most common sites of infection were: bronchia, genitourinary tract and oral cavity. Clinically it was determined that 44 were bacterial infections, 3 fungal, 2 viral and 2 combined. Discussion: it draws our attention the predominance of patients from low socioeconomic and educational levels. While infections may correspond to potentially fatal complications in cancer patients, the majority of our cases were mild.

Morphological changes of Candida albicans induced by saperconazole.

The effects of a new triazole antifungal agent, saperconazole, on the morphology of Candida albicans were studied by scanning and transmission electron microscopy. An inoculum of 10(6) CFU ml-1 was exposed to saperconazole at 1 and 10 micrograms ml-1 and at different times up to 24 h samples were removed for microscopic observations. The antifungal agent caused the yeasts to become round and turgescent and to cluster; budding appeared to be affected also, as seen by scanning electron microscopy. Transmission electron microscopy showed a thickened wall, the presence of intraparietal electron-dense vesicles and of multilamellae near the plasma membrane.

Significance of cytomegalovirus (CMV)-pp65 antigenemia in the diagnosis of CMV disease in human immunodeficiency virus-infected patients.

To establish the diagnostic value of the cytomegalovirus (CMV)-pp65 antigenemia in CMV disease occurring in human immunodeficiency (HIV)-infected patients, CMV-pp65 antigen in polymorphonuclear leukocytes (PMNLs) was assayed in 373 samples from 138 randomly included patients followed up for symptomatic HIV-1 infection and the correlation between CMV-pp65 antigenemia and diagnosis of CMV disease was investigated. Thirty-seven CMV disease episodes were observed in 30 patients and 89.2% of these episodes were associated with a positive CMV-pp65 antigenemia. In contrast, 94% of the patients negative for CMV-pp65 antigenemia remained free of CMV disease. Patients with CMV disease had significantly higher levels of CMV-pp65 antigenemia than CMV disease-free patients (695 positive cells/2 x 10(5) PMNLs vs. 28 positive cells/2 x 10(5) PMNLs). The positive and negative predictive values of the test were 45% and 94%, respectively, but were 93% and 80%, respectively, when a CMV-pp65 antigenemia level of > 100 positive cells/2 x 10(5) PMNLs was taken into consideration. These results indicate that the CMV-pp65 antigenemia assay is useful for the diagnosis and monitoring of CMV disease in HIV-infected patients.

Evaluation of the Nuclisens HIV-1 QT assay for quantitation of human immunodeficiency virus type 1 RNA levels in plasma.

Nuclisens HIV-1 QT is a new version of the NASBA HIV-1 QT assay for quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in plasma. The specificity of this assay was 100% in one laboratory and 99%-with nonrepeatability of the initial false positive-in another. The test was linear between 2.0 and 6.0 log RNA copies per ml. According to the input HIV-1 RNA concentration, accuracy varied from -0.11 to +0.10 log RNA copy per ml and precision varied from 0.66 to 0.14 log RNA copy per ml. Reproducibility decreased when the HIV-1 RNA level was near the lower limit of quantitation of the test. HIV-1 RNA could be quantitated by Nuclisens HIV-1 QT in 36% (laboratory 1) and 24% (laboratory 2) of clinical samples with HIV-1 RNA levels lower than the lower limit of quantitation by NASBA HIV-1 QT. Nuclisens HIV-1 QT was not suitable for measurement of RNA from clade G and group O HIV-1 strains.

Single dose pharmacokinetics of fenspiride hydrochloride: phase I clinical trial.

The absolute bioavailability of fenspiride has been studied in twelve healthy volunteers. It was administered IV and orally in single doses of 80 mg fenspiride hydrochloride according to a randomised crossover pattern. Following IV administration, the plasma clearance of fenspiride was about 184 ml.min-1, and its apparent volume of distribution was moderately large (215 l). When given orally as a tablet, fenspiride exhibited fairly slow ab- sorption; the maximum plasma concentration (206 ng.ml-1) was achieved 6 h after administration. The absolute bioavailability was almost complete (90%). The tablet had slow release characteristics. The elimination half-life obtained from the plasma data was 14 to 16 h independent of the route of administration.

[In vitro effect of itraconazole against various species of Candida]. / Activité in vitro de l'itraconazole sur diverses espèces de Candida.

The authors compared the in vitro antifungal activity of itraconazole to that of miconazole against various species of Candida. The MIC of 88 strains of Candida (C. albicans, C. guilliermondii, C. parapsilosis, C. glabrata) was determined by the agar dilution method using casitone medium at pH 5.5-5.6 for miconazole and pH 7.2-7.4 for itraconazole. C. albicans and C. glabrata were found to be less sensitive in vitro to itraconazole than to miconazole; the contrary was observed for C. parapsilosis. The sensitivity of C. guilliermondii to these antifungal agents was similar. The MIC 50, MIC 90 and G.MIC values for itraconazole with respect to 42 strains of C. albicans was 0.10, 1.4 and 0.138 micrograms ml-1, respectively; the MIC 90 and G.MIC values for miconazole were 0.5 and 0.021 micrograms ml-1, respectively. The effect of itraconazole on the ultrastructure of C. albicans yeast cells and spheroplasts was studied by scanning electron microscopy. This triazole molecule modified the cell wall of C. albicans, caused cell stretching and provoked defective separation between mother and daughter cells. Itraconazole altered the cytoplasmic membrane of the spheroplasts causing them to have a "spongy" appearance. Yeast cells treated with itraconazole appeared to liberate their spheroplast with difficulty.

[Comparative action of 8 azole derivatives against Candida albicans: fungistatic action and cytologic study by scanning electron microscopy]. / Activité comparée de huit composés azolés sur Candida albicans: pouvoir fongistatique et cytologie en microscopie électronique à balayage.

The authors compared the in vitro antifungal activity of eight imidazole derivatives (clotrimazole, econazole, isoconazole, ketoconazole, miconazole, oxiconazole, terconazole, tioconazole) against 42 strains of Candida albicans by the agar dilution method using casitone medium. The geometric (G) mean MIC values, the MIC 90 and the MIC 50 values and the corresponding standard deviations of each antifungal agent were determined. The G-MIC values were found to be in the range of 0.008-0.390 micrograms ml-1. The effects of these eight antifungal agents on the ultrastructure of C. albicans yeast cells and spheroplasts were studied by scanning electron microscopy (SEM). The results showed a good correlation between the lesions observed and the structure of the imidazole derivatives tested. On the basis of the SEM results, the compounds could be divided into three groups: (1) ketoconazole and terconazole; (2) econazole, isoconazole, miconazole, oxiconazole and tioconazole; (3) clotrimazole.