How do we classify a central tumor? Results of a multidisciplinary survey from the SEPAR Thoracic Oncology area / ¿Cómo clasificamos un tumor central? Resultados de una encuesta multidisciplinaria propuesta desde el área de Oncología Torácica de SEPAR

Introduction: In patients with non-small cell lung cancer (NSCLC) and normal mediastinal imaging tests, centrally located tumors have greater occult mediastinal involvement. Clinical guidelines, therefore, recommend invasive mediastinal staging in this situation. However, definitions of centrality in the different guidelines are inconsistent. The SEPAR Thoracic Oncology area aimed to evaluate the degree of familiarity with various concepts related to tumor site among professionals who see patients with NSCLC in Spain.Methods: A questionnaire was distributed to members of Spanish medical societies involved in the management of NSCLC, structured according to the 3 aspects to be evaluated: 1) uniformity in the definition of central tumor location; 2) uniformity in the classification of lesions that extend beyond dividing lines; and 3) ability to delineate lesions in the absence of dividing lines.Results: A total of 430 participants responded. The most voted definition of centrality was «lesions in contact with hilar structures» (49.7%). The lines most often chosen to delimit the hemithorax were concentric hilar lines (89%). Most respondents (92.8%) classified tumors according to the side of the dividing line that contained most of their volume. Overall, 78.6% were able to correctly classify a central lesion in the absence of dividing lines.Conclusions: In our survey, the most widely accepted definition of centrality is not one of the proposals specified in the clinical guidelines. The results reflect wide variability in the classification of tumor lesions. (AU)

Introducción: En pacientes con cáncer de pulmón de célula no pequeña (CPCNP) y mediastino normal, en pruebas de imagen, los tumores de localización central presentan mayor afectación mediastínica oculta. Por ello las guías clínicas recomiendan estadificación mediastínica invasiva en esta situación. No obstante, las definiciones de centralidad son poco uniformes entre guías. Desde el área de oncología torácica de la SEPAR se propuso evaluar el grado de familiaridad con varios conceptos relacionados con la localización tumoral entre profesionales que atienden pacientes con CPCNP en nuestro territorio.Métodos: Se envió una encuesta a miembros de sociedades médicas nacionales implicadas en el manejo del CPCNP. La encuesta se estructuró en tres aspectos a evaluar: 1) uniformidad en la definición de localización tumoral central; 2) uniformidad en la clasificación de lesiones que sobrepasan líneas divisorias y 3) capacidad para delimitar lesiones en ausencia de líneas divisorias.Resultados: 430 participantes respondieron. La definición de centralidad más votada fue «lesiones en contacto con las estructuras hiliares» (49,7%). Las líneas más escogidas para delimitar el hemitórax fueron líneas concéntricas al hilio (89%). La mayoría (92,8%) consideró los tumores según en qué lado de la línea divisoria se encontrase la mayor parte de su volumen. Un 78,6% fue capaz de catalogar correctamente una lesión central en ausencia de líneas divisorias.Conclusiones: En nuestra encuesta, la definición de centralidad más aceptada no es ninguna de las propuestas en las guías clínicas. Los resultados reflejan amplia variabilidad para clasificar lesiones tumorales. (AU)

Recent infections among newly diagnosed cases of HIV infection in Spain, 2015-2016. National estimates using cohort data.

BACKGROUND: To estimate the prevalence of recent infection (RI) among people newly diagnosed with HIV in Spain using a representative sample collected by the AIDS Research Network cohort (CoRIS) during 2015-2016. METHODS: Stratified sampling of CoRIS data was used with proportional allocation by mode of transmission of new HIV diagnoses notified to National Surveillance System. Samples used were from patients in the CoRIS cohort with available stored plasma collected within 6 months after diagnosis. Weighted methods were used to estimate the prevalence of RI and multivariate logistic regression models were used to determine associated factors. RESULTS: Of the 669 individuals included, 55.1% were men who had sex with men (MSM), 24.6% were heterosexual, and 20.3% were non-MSM non-heterosexual. The weighted prevalence of RI was 11.8% (95% Confidence interval [CI] 9.4-14.8%) overall, 15.5% (12.2-19.4%) among MSM, 6.3% (3.9-10.0%) among heterosexual, and 8.6% (3.2-20.9%) in non-MSM non-heterosexual persons. Factors associated with prevalence of RI were: MSM (OR 2.05; 95% CI 1.02-4.14) vs. heterosexual, being Spanish (OR 2.92; 1.36-6.26) or European (OR 3.42; 1.28-9.13) vs. Latin American, having a secondary or higher education level (OR 3.08; 0.95-1.00) vs. primary, and having a CD4 count of 350-499 (OR 3.26; 1.46-7.30) or >500 (OR 6.26; 2.92-13.39) vs. <350 cells/mm3. CONCLUSIONS: In the absence of direct data from surveillance systems, the use of cohort data is a very valuable option for identifying the prevalence of RI at national level. This is the first nationwide study carried out in Spain to determine the prevalence of RI using an avidity assay.

How do we Classify a Central Tumor? Results of a Multidisciplinary Survey from the SEPAR Thoracic Oncology Area. / ¿Cómo clasificamos un tumor central? Resultados de una encuesta multidisciplinaria propuesta desde el área de Oncología Torácica de SEPAR.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) and normal mediastinal imaging tests, centrally located tumors have greater occult mediastinal involvement. Clinical guidelines, therefore, recommend invasive mediastinal staging in this situation. However, definitions of centrality in the different guidelines are inconsistent. The SEPAR Thoracic Oncology area aimed to evaluate the degree of familiarity with various concepts related to tumor site among professionals who see patients with NSCLC in Spain. METHODS: A questionnaire was distributed to members of Spanish medical societies involved in the management of NSCLC, structured according to the 3 aspects to be evaluated: 1) uniformity in the definition of central tumor location; 2) uniformity in the classification of lesions that extend beyond dividing lines; and 3) ability to delineate lesions in the absence of dividing lines. RESULTS: A total of 430 participants responded. The most voted definition of centrality was «lesions in contact with hilar structures¼ (49.7%). The lines most often chosen to delimit the hemitorax were concentric hilar lines (89%). Most participants (92.8%) classified tumors according to the side of the dividing line that contained most of their volume. Overall, 78.6% were able to correctly classify a central lesion in the absence of dividing lines. CONCLUSIONS: In our survey, the most widely accepted definition of centrality is not one of the proposals specified in the clinical guidelines. The results reflect wide variability in the classification of tumor lesions.

Geometrical Measurement of Central Tumor Location in cT1N0M0 NSCLC Predicts N1 but Not N2 Upstaging.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC) and normal mediastinum, the central tumor location predicts occult nodal disease (both N1 and N2). We evaluated a novel definition of central location based on a geometrical measurement of the tumor location within the lung that could predict N2, N1, or both. METHODS: This retrospective study included patients with confirmed NSCLC, radiologically and metabolically staged T1 N0 M0, who underwent invasive mediastinal staging and/or lung resection. The central tumor location was measured considering 2 ratios. The inner margin ratio (IMR) and outer margin ratio (OMR) were both calculated as the distance from the inner margin of the lung to both margins of the tumor (inner [IMR], outer [OMR]) divided by the lung width. Optimal cutoffs for IMR and OMR were calculated. Tumors with values lower than the cutoffs were considered central. Prevalences of N1 and N2 upstaging were estimated and bivariate logistic regression analysis was performed to predict the odds of N1 and N2 upstaging using IMR and OMR cutoffs. RESULTS: A total of 209 patients were included. The prevalence of N1 and N2 upstaging was 11% and 5.3%, respectively. Cutoffs of 0.5 for IMR and 0.64 for OMR were estimated. Both ratios predicted N1 upstaging (adjusted odds ratio [95% confidence interval]: 4.2 [1.5-12]; P < .007; area under the curve, 0.65) but did not predict N2 upstaging. CONCLUSIONS: Central tumor location can be assessed by means of IMR and OMR and predicts N1 upstaging in patients with radiologically and metabolically T1 N0 M0 tumors. This is important for the selection of patients for therapies that require N0 tumors.

Higher accuracy of genotypic identification compared to phenotyping in the diagnosis of coagulase-negative staphylococcus infection in orthopedic surgery.

PURPOSE: To determine whether Repetitive Extragenic Palindromic PCR (rep-PCR) genotyping can improve the diagnosis of coagulase-negative staphylococcal (CoNS) orthopaedic infections in comparison to phenotyping. METHODS: Prospective study comparing the results of phenotypic/genotypic (rep-PCR) testing in patients with suspected CoNS infection. Each strain was analysed using both methods. Strains identified as identical in ≥2 samples were considered as pathogenic. RESULTS: 255 CoNS strains from 52 surgical episodes were included. Infection was diagnosed by phenotyping in 38(73%) cases and by genotyping in 40(77%). The Kappa index was 0.59. Sensitivity, Specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for phenotyping (vs. rep-PCR) were: 88%, 75%, 92%, and 64%. 5/14(36%) of cases not considered as true infections by phenotyping were diagnosed as infections with genotyping. In a subgroup of 203 strains from 41 surgical procedures with orthopaedic implants, the kappa index was 0.68. Sensitivity, Specificity, PPV, and NPV for phenotyping were: 93%, 73%, 90% and 80%. Again, 2/10 episodes in which CoNS were considered non-infective by phenotyping were diagnosed as infected by genotyping. CONCLUSIONS: Rep-PCR genotyping can identify identical CoNS strains that differ in their phenotype and should be used as a complementary technique. One-third of infected cases may be misdiagnosed without genotypic analysis.

Concordance Between Rapid On-Site Evaluation and Final Cytologic Diagnosis in Patients Undergoing Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Non-Small Cell Lung Cancer Staging.

OBJECTIVES: In patients with lung cancer undergoing mediastinal staging through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), decisions are based on rapid on-site evaluation (ROSE) findings. We aimed to analyze the concordance rate between ROSE diagnosis and final diagnosis. METHODS: A prospective study was carried out in patients undergoing EBUS-TBNA for lung cancer staging. Diagnosis concordance was defined as cases where lymph nodes (LNs) presented the same diagnosis in ROSE and final diagnosis. Determinants of concordance were analyzed. RESULTS: Sixty-four patients were included and 637 LNs sampled. ROSE diagnosis was concordant with final diagnosis in 612 (96.1%) LNs and nonconcordant in 25 (3.9%). Differences in the concordance rate were found between pathologists, ROSE diagnoses, presence of cell block, number of passes, and number of slides. The staging status was changed between ROSE and the final diagnosis in three (4.6%) patients. CONCLUSIONS: ROSE diagnosis has a high concordance with the final diagnosis.

Nodal size ranking as a predictor of mediastinal involvement in clinical early-stage non-small cell lung cancer.

In non-small cell lung cancer (NSCLC) patients, the recommended minimum requirement for an endoscopy-based mediastinal staging procedure is sampling the largest lymph node (LN) in right and left inferior paratracheal, and subcarinal stations. We aimed to analyze the percentage of cases where the largest LN in each mediastinal station was malignant in a cohort of NSCLC patients with mediastinal metastases diagnosed in the lymphadenectomy specimen. Furthermore, we investigated the sensitivity of a preoperative staging procedure in a hypothetical scenario where only the largest LN of each station would have been sampled.Prospective data of patients with mediastinal nodal metastases diagnosed in the lymphadenectomy specimens were retrospectively analyzed. The long-axis diameter of the maximal cut surface of all LNs was measured on hematoxylin and eosin-stained sections.Seven hundred seventy five patients underwent operation and 49 (6%) with mediastinal nodal disease were included. A total of 713 LNs were resected and 119 were involved. Sixty seven nodal stations revealed malignant LNs: in these, the largest LN was malignant in 39 (58%). In a "per patient" analysis, a preoperative staging procedure that sampled only the largest LN would have attained a sensitivity of 0.67; and if the largest and the second largest were sampled, sensitivity would be 0.87.In patients with NSCLC, nodal size ranking is not reliable enough to predict malignancy. In clinical practice, regardless of the preoperative staging method, systematic thorough sampling of all visible LNs is to be recommended over selective random samplings.

Utilidad del Quantiferon-TB Gold in Tube en el cribado de la infección latente tuberculosa en personal sanitario / Usefulness of Quantiferon-TB Gold in Tube in screening for latent tuberculosis infection in health workers

INTRODUCCIÓN: El personal sanitario se considera un colectivo de riesgo por estar más expuesto a la enfermedad tuberculosa. La prueba de la tuberculina (PT) presenta el inconveniente del alto número de falsos positivos, sobre todo en pacientes vacunados con BCG. En los últimos años las técnicas denominadas IGRAS parecen mejorar estos inconvenientes, si bien plantean otros dilemas. Nuestro objetivo es analizar la concordancia de ambos test y realizar un estudio de coste-beneficio de las posibles estrategias diagnósticas. MATERIAL Y MÉTODOS: Entre enero de 2010 y octubre de 2011 se estudió todo el personal sanitario del Hospital Universitari Mútua Terrassa de nueva incorporación y aquellos que tenían su revisión laboral. También se estudiaron trabajadores que habían sido contactos de pacientes ingresados con tuberculosis, sin aislamiento inicial. En todos los casos se realizó la PT y paralelamente un Quantiferon-TB Gold in Tube® (QF-G-IT) en sangre. Se consideró positiva una PT ≥ 10 mm y un QF-G-IT > 0,35 IU/ml. Se descartó enfermedad tuberculosa en todos los profesionales mediante radiología de tórax. Se hizo un estudio de coste beneficio de 3 estrategias posibles de estudio de la infección latente tuberculosa (ILT). RESULTADOS: Se estudiaron 226 profesionales sanitarios, con una media de edad de 30,65 ± 16 años. Cuarenta y cuatro (19,4%) presentaban vacuna con BCG, y en 8 (3,5%) se desconocía. La PT fue positiva en 33 (14,6%) casos y el QF-G-IT en 17 (7,5%). En 15 casos ambos valores de la PT y del QF-G-IT fueron positivos y coincidentes. En 18 (8%) profesionales la PT fue positiva, con un valor de QF-G-IT negativo. La concordancia entre ambas pruebas fue del 91%, con un kappa de 0,55. En vacunados, la concordancia fue del 70,5%, con un kappa de 0,33, mientras que en no vacunados fue del 98,9%, con un kappa de 0,65. La estrategia de cribado de la ILT más económica fue la basada en la PT, pero seguida muy de cerca por la estrategia basada en la PT con reconfirmación de los positivos con QF-G-IT, que fue la que mostró un mejor coste-beneficio ya que reduce profilaxis innecesarias. CONCLUSIONES: El QF-G-IT parece ser una técnica adecuada en la detección de la ILT y permite detectar los falsos positivos de la PT debidos a la vacuna con BCG. En este colectivo el QF-G-IT podría ser la prueba idónea para detectar a los realmente infectados y evitar así quimioprofilaxis innecesarias. La estrategia que mostró ser más coste-beneficio fue la basada en la PT con reconfirmación de los casos positivos mediante QF-G-IT

INTRODUCTION: Healthcare workers (HW) are considered a risk group for exposure to tuberculosis. Screening for latent tuberculosis infection (LTBI) is mandatory in all HW. The Tuberculin test (TT) has been used up until now for LTBI screening, but gives a high number of false positives, especially in patients vaccinated with BCG. Diagnostic methods based on detection of specific gamma interferon (IGRA) have recently appeared on the market in order to improve these drawbacks, but pose other dilemmas. The aim of this study is to determine the agreement between the two types of test and to carry out a cost-benefit study of the possible diagnostic strategies. MATERIAL AND METHODS: All newly hired HW by the Hospital Universitari Mútua Terrassa between January 2010 and October 2011 we were included in the study, as well as those who had their occupational review. Workers who been in contact with patients admitted with tuberculosis before the initial isolation were also tested. In all cases a parallel TT and serum QuantiFeron-TB Gold-in-Tube® (QF-G-IT) assays were performed. TB disease was ruled out in all professional by chest X-ray. The TT was considered positive when it was equal to or more than 10 mm and if the QF-G-IT was 0.35 IU/mL. A cost-effectiveness analysis was designed with three possible strategies to detect LTBI in order to find the one with the best cost-benefit. RESULTS: A total of 226 HW were studied, with a mean age 30.65 ± 16, of whom 44 (19.4%) had previous BCG vaccination history, and 8 (3.5%) unknown. The TT was positive in 33 (14.6%) cases and the QF-G-IT in 17 (7.5%). The values of the TT and QF-G-IT were both positive in 15 cases. In 18 (8%) The TT was positive in 18 (8%) of cases with a negative QF-G-IT value. The agreement between the two tests was 91%, with a Kappa of 0.55. In vaccinated cases, the correlation was 70.5%, with a Kappa of 0.33, while in unvaccinated it was 98.9% with a Kappa of 0.65. The cheapest screening strategies for LTBI diagnosis were hose based on TT, but followed closely by the strategy based on TT with reconfirmation of positives with QF-G-IT. CONCLUSIONS: QF-G-IT seems to be a very sensitive technique to detect LTBI and allows false positives due to TT to be detected, particularly in BCG vaccinated HW. In this group QF-G-IT could be the ideal test to detect truly infected staff, and avoid unnecessary chemoprophylaxis. The most cost-benefit strategy was those based in TT with reconfirmation or rejection of positive cases by QF-G-IT

[Usefulness of Quantiferon-TB Gold in Tube® in screening for latent tuberculosis infection in health workers]. / Utilidad del Quantiferon-TB Gold in Tube(®) en el cribado de la infección latente tuberculosa en personal sanitario.

INTRODUCTION: Healthcare workers (HW) are considered a risk group for exposure to tuberculosis. Screening for latent tuberculosis infection (LTBI) is mandatory in all HW. The Tuberculin test (TT) has been used up until now for LTBI screening, but gives a high number of false positives, especially in patients vaccinated with BCG. Diagnostic methods based on detection of specific gamma interferon (IGRA) have recently appeared on the market in order to improve these drawbacks, but pose other dilemmas. The aim of this study is to determine the agreement between the two types of test and to carry out a cost-benefit study of the possible diagnostic strategies. MATERIAL AND METHODS: All newly hired HW by the Hospital Universitari Mútua Terrassa between January 2010 and October 2011 we were included in the study, as well as those who had their occupational review. Workers who been in contact with patients admitted with tuberculosis before the initial isolation were also tested. In all cases a parallel TT and serum QuantiFeron-TB Gold-in-Tube(®) (QF-G-IT) assays were performed. TB disease was ruled out in all professional by chest X-ray. The TT was considered positive when it was equal to or more than 10mm and if the QF-G-IT was 0.35 IU/mL. A cost-effectiveness analysis was designed with three possible strategies to detect LTBI in order to find the one with the best cost-benefit. RESULTS: A total of 226 HW were studied, with a mean age 30.65 ± 16, of whom 44 (19.4%) had previous BCG vaccination history, and 8 (3.5%) unknown. The TT was positive in 33 (14.6%) cases and the QF-G-IT in 17 (7.5%). The values of the TT and QF-G-IT were both positive in 15 cases. In 18 (8%) The TT was positive in 18 (8%) of cases with a negative QF-G-IT value. The agreement between the two tests was 91%, with a Kappa of 0.55. In vaccinated cases, the correlation was 70.5%, with a Kappa of 0.33, while in unvaccinated it was 98.9% with a Kappa of 0.65. The cheapest screening strategies for LTBI diagnosis were those based on TT, but followed closely by the strategy based on TT with reconfirmation of positives with QF-G-IT. CONCLUSIONS: QF-G-IT seems to be a very sensitive technique to detect LTBI and allows false positives due to TT to be detected, particularly in BCG vaccinated HW. In this group QF-G-IT could be the ideal test to detect truly infected staff, and avoid unnecessary chemoprophylaxis. The most cost-benefit strategy was those based in TT with reconfirmation or rejection of positive cases by QF-G-IT.

Quejas cognitivas en personas con infección por el virus de la inmunodeficiencia humana en España: prevalencia y variables relacionadas / Cognitive complaints in people with human immunodeficiency virus in Spain: prevalence and related variables

Fundamento y objetivo: La existencia de quejas cognitivas en personas con VIH ha sido poco estudiada en España. El objetivo de este estudio fue conocer la prevalencia de quejas cognitivas en personas con VIH, así como sus posibles relaciones con variables demográficas, clínicas y psicológicas, en la época de los tratamientos antirretrovirales combinados. Pacientes y método: Estudio multicéntrico observacional desarrollado en 4 hospitales y 10 ONGs en el que participaron 791 personas con VIH en España. Para la recogida de datos se utilizó un cuestionario autorreferido que evaluó variables demográficas y clínicas, e incluyó también la evaluación de quejas cognitivas, el estado emocional y la calidad de vida. El análisis de datos incluyó pruebas estadísticas descriptivas e inferenciales. Resultados: Casi la mitad de la muestra (49,8%) manifestó quejas cognitivas, un 72,1% hallando relación con interferencia en la vida diaria. La memoria y la concentración fueron las áreas más percibidas como alteradas. La presencia de queja cognitiva se relacionó significativamente con un mayor tiempo de infección, un menor número de CD4, carga viral indetectable y peor calidad de vida. Un análisis discriminante mostró que la depresión, la ansiedad, una mayor edad, estar sin pareja y un bajo nivel de estudios fueron las variables que permitieron clasificar mejor a las personas con VIH y queja cognitiva. Conclusiones: Las quejas cognitivas son frecuentes en personas con VIH en la época de los tratamientos antirretrovirales combinados. Este hecho está relacionado con una peor salud psicológica y calidad de vida, así como con un peor estado inmunológico y virológico (AU)

Background and objective Cognitive complaints have been scarcely studied in people with HIV in Spain. The aim of this research was to know the prevalence of cognitive complaints in HIV-infected people, as well as its potential relationships with demographic, clinical and psychological variables, in the era of combination antiretroviral therapies. Patients and method Observational multicenter study developed in 4 hospitals and 10 NGOs, in which 791 people with HIV in Spain participated. A self-reported questionnaire was used to evaluate demographic and clinical variables, and an assessment of cognitive complaints, emotional status and quality of life variables was also included. Descriptive and inferential tests were used for statistical analyses. Results Almost half of the sample (49.8%) referred cognitive complaints, in 72.1% of them an association with interference on daily living activities was found. Memory and attention were the areas most prevalently perceived as affected. The existence of cognitive complaints correlated with a longer HIV infection, lower CD4+ cell count, undetectable viral load and worse quality of life. A discriminant analysis determined that depression, anxiety, older age, living with no partner and low education level allowed to classify optimally HIV-infected people with cognitive complaints. Conclusions Self-reported cognitive complaints are frequent in people infected with HIV in the current era of combination antiretroviral therapies. This fact is related to emotional disturbances and poor quality of life, but also to impaired immunological and virological status (AU)

[Cognitive complaints in people with human immunodeficiency virus in Spain: prevalence and related variables]. / Quejas cognitivas en personas con infección por el virus de la inmunodeficiencia humana en España: prevalencia y variables relacionadas.

BACKGROUND AND OBJECTIVE: Cognitive complaints have been scarcely studied in people with HIV in Spain. The aim of this research was to know the prevalence of cognitive complaints in HIV-infected people, as well as its potential relationships with demographic, clinical and psychological variables, in the era of combination antiretroviral therapies. PATIENTS AND METHOD: Observational multicenter study developed in 4 hospitals and 10 NGOs, in which 791 people with HIV in Spain participated. A self-reported questionnaire was used to evaluate demographic and clinical variables, and an assessment of cognitive complaints, emotional status and quality of life variables was also included. Descriptive and inferential tests were used for statistical analyses. RESULTS: Almost half of the sample (49.8%) referred cognitive complaints, in 72.1% of them an association with interference on daily living activities was found. Memory and attention were the areas most prevalently perceived as affected. The existence of cognitive complaints correlated with a longer HIV infection, lower CD4+ cell count, undetectable viral load and worse quality of life. A discriminant analysis determined that depression, anxiety, older age, living with no partner and low education level allowed to classify optimally HIV-infected people with cognitive complaints. CONCLUSIONS: Self-reported cognitive complaints are frequent in people infected with HIV in the current era of combination antiretroviral therapies. This fact is related to emotional disturbances and poor quality of life, but also to impaired immunological and virological status.

Monitoring HIV viral load in resource limited settings: still a matter of debate?

INTRODUCTION: Consequences of lack of viral monitoring in predicting the effects of development of HIV drug resistance mutations during HAART in resource-limited settings (RLS) is still a matter of debate. DESIGN: To assess, among HIV+ patients receiving their first-line HAART, prevalence of virological failure and genotypic resistance mutations pattern in a Médécins Sans Frontières/Ministry of Health programme in Busia District (Kenya). METHODS: Patients with HAART treatment for ≥12 months were eligible for the study and those with HIV-RNA ≥5000 copies/ml underwent genotypic study. Total HIV-1 RNA from Dried Blood Spots was extracted using Nuclisens method. RESULTS: 926 patients were included. Among 274 (29.6%) patients with detectable viral load, 55 (5.9%) experienced treatment failure (viral load >5.000 copies/ml); 61.8% were female and 10 (18.2%) had clinical failure. Median CD4 cell count was 116 cell/mm3 (IQR: 54-189). Median HIV-RNA was 32,000 copies/ml (IQR: 11000-68000). Eighteen out of 55 (33%) samples could be sequenced on PR and RT genes, with resistance associated mutations (RAMs) in 15 out of 18 samples (83%). Among patients carrying RAMs, 12/15 (81%) harboured RAMs associated to thymidine analogues (TAMs). All of them (100%) showed M184V resistance associated mutation to lamivudine as well as NNRTI's RAMS. CONCLUSIONS: Virological failure rate in resource-limited settings are similar to those observed in developed countries. Resistance mutation patterns were concordant with HAART received by failing patients. Long term detectable viral load confers greater probability of developing resistance and as a consequence, making difficult to find out a cost-effective subsequent treatment regimen.

Clinical, virological and biochemical evidence supporting the association of HIV-1 reverse transcriptase polymorphism R284K and thymidine analogue resistance mutations M41L, L210W and T215Y in patients failing tenofovir/emtricitabine therapy.

BACKGROUND: Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. RESULTS: The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. CONCLUSIONS: Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

Sensitivity of seven HIV subtyping tools differs among subtypes/recombinants in the Spanish cohort of naïve HIV-infected patients (CoRIS).

BACKGROUND: HIV-1 group M is classified into 9 subtypes and recombinants (CRFs/URFs). Variants other than subtype B (non-B) cause 90% of infections worldwide. HIV is often subtyped using automated tools instead of the gold-standard phylogenetic analysis. We evaluated the reliability of subtyping tools vs. phylogeny in a panel of HIV-1 pol sequences from the cohort of naïve patients of the HIV/AIDS Spanish Research Network (CoRIS). METHODS: HIV-1 subtyping was performed using seven automated subtyping tools (Stanford, Geno2pheno, Rega, NCBI, EuResist, STAR, TherapyEdge) in HIV-1 pol sequences from 670 CoRIS patients previously subtyped by phylogeny (587 subtype B/83 non-B). Sensitivity with respect to phylogeny was assessed. RESULTS: Most tools correctly classified subtype B, although up to 15% of non-B sequences were wrongly identified as B depending on the tool. For subtype B and CRF02_AG identification, Stanford/NCBI and Geno2pheno/Rega presented the highest/lowest sensitivities, respectively. EuResist and Geno2pheno correctly classified all 13 non-B "pure"subtypes at pol. The efficacy of all subtyping tools dropped clearly when identifying recombinants different from CRF02_AG. Only NCBI05, Rega and STAR identified URF, but with very low sensitivities. NCBI classified the highest number of subtypes B as non-B, and overestimated recombinants, especially when including references of 2009. CONCLUSIONS: Automated tools are useful for subtype B identification, although they present serious limitations in classifying variants uncommon in developed regions, especially recombinants. Their sensitivity depends on the prevalence of non-B variants in the population, and decreases drastically when the frequency of recombinants increases. Furthermore, HIV-1 variant distribution differs according to the tool used.

Respuesta. ¿PISCIS en aguas turbulentas? / Reply. PISCIS in turbulent waters?

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Relations between respiratory symptoms and spirometric values in young adults: the European community respiratory health study.

We aim to assess whether respiratory symptoms are associated with lung function in young adults, and whether any such relation is similar in those with asthma, in men and women, and in different countries. Study participants (aged 20-44 years) were randomly selected from the general population in 35 centres in 15 countries as part of the European Community Respiratory Health Study. In all, 12,541 subjects (47%) completed a respiratory symptoms questionnaire and spirometry, metacholine challenge and immunoglobulin E tests. Indicators of diagnosed asthma showed the largest association with airways obstruction (FEV1--maximal 1-s forced expiratory volume/forced vital capacity--FVC < 70%), followed by symptoms of wheezing or shortness of breath, in both genders. Among the 96% of subjects whose FEV1/FVC ratios were greater or equal to 70%, wheezing or shortness of breath was associated with lower FEV1 levels (-211 ml in men and -169 ml in women (P < 0.01)), independent of diagnosed asthma, smoking, atopy or bronchial responsiveness. This association was not explained by a lower FVC. Symptoms of chronic bronchial mucus hypersecretion (chronic phlegm) were unrelated to both airways obstruction and FEV1 levels. Findings were homogeneous across all centres. These results suggest that lung diseases that cause wheezing are generally associated with impaired lung function.