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1.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
2.
Acta Ophthalmol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421336

RESUMO

PURPOSE: To report the incidence and quantity of silicone oil microbubbles and the relationship with the number of intravitreal anti-vascular endothelial growth factor (VEGF) injections and evaluate if microbubbles induce artefacts on optical coherence tomography (OCT) images. METHODS: Observational, descriptive, cross-sectional study. Patients with wet age-related macular degeneration were included who had been treated for 1 year minimally with anti-VEGF injections repackaged in the hospital pharmacy. Detection and quantification of silicone microbubbles by mydriatic biomicroscopic examination were conducted 1 month after the last injection. The numbers of microbubbles were quantified on a scale of 0-3: 0, none; 1 scarce (1-10 microbubbles); 2 moderate (10-30); or 3 numerous (>30). Shadowing on OCT images was classified as 0-3: 0, none; 1 obscuring some retinal layers; 2 obscuring all retinal layers; or 3 obscuring the retinal thickness. RESULTS: The study included 142 eyes of 98 patients (mean age, 82.4 years + 7.3; range, 65-97) treated with 2377 injections. Microbubbles were detected in 127 (89.4%) eyes, 62 (43.6%) with numerous microbubbles and 36 (25.4%) and 29 (20.4%), respectively, with scarce and moderate numbers. A positive correlation was found between the numbers of injections and intravitreal silicone (rho, 0.7). Optical coherence tomography (OCT) artefacts were detected in 11 eyes; the artefacts obscured all retinal layers in three eyes. No significant relationship could be established between the appearance of floaters and the microbubbles. CONCLUSION: The presence and number of silicone microbubbles were correlated with the number of intravitreal injections. Microbubbles can produce OCT artefacts, which can hinder the treatment decision.

3.
Int J Gynecol Cancer ; 31(4): 617-622, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33318079

RESUMO

BACKGROUND: Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity. PRIMARY OBJECTIVE: To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months. TRIAL DESIGN: The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1. PRIMARY ENDPOINT: The primary endpoint for this study is progression free survival. SAMPLE SIZE: Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023. TRIAL REGISTRATION: Clinicaltrials.gov NCT03598270.

5.
PLoS One ; 15(9): e0238575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941476

RESUMO

OBJECTIVE: Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. DESIGN: Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. METHODS: We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. RESULTS: Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. CONCLUSIONS: The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. CLINICAL TRIALS REGISTRATION: NCT02577042.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Imunossenescência/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Raltegravir Potássico/administração & dosagem
6.
Br J Clin Pharmacol ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32852102

RESUMO

AIMS: To determine the prevalence of potential prescribing issues (PPI) in HIV-infected subjects aged ≥65 years according to the Beers and STOPP/START criteria and antiretroviral drug-drug interactions (Liverpool website). Secondary objectives were to assess the concordance between Beers and STOPP/START criteria in our population, and to identify the drugs most frequently involved in PPI. METHODS: Cross-sectional cohort study based on a systematic review of the electronic drug prescriptions confirmed by an interview of 91 HIV-infected patients aged ≥65 years. Discrepancies between prescription criteria were assessed using crosstabs and compared using the χ2 test or Fisher exact test. RESULTS: The mean age was 72.1 (5.6) years, 75.8% had ≥3 comorbidities and 59.3% polypharmacy. PPI were identified in 87.9%: 71.4% by STOPP/START and 45.1% by Beers. Comparing both criteria, 56.9% of PPI by STOPP/START were detected by Beers, while 92.5% of those detected by the Beers criteria were detected by STOPP/START (P < .001). Amber/red flag interactions between antiretrovirals and comedications were found in 45.1%: 3 severe (red) in 2 patients (2.2%). The most frequent drugs involved in PPI were benzodiazepines (>30%). Cobicistat was the drug most frequently involved in potential interactions (42.2%). CONCLUSION: The prevalence of PPI among older HIV-infected persons gives cause for concern, as it is almost 90%. Optimization strategies, including a critical review of the treatment plan, should be implemented in clinical routine by a multidisciplinary team, in particular in patients with multiple comorbidities and polypharmacy. The STOPP/START criteria seem to detect more PPI, mainly for European populations.

8.
AIDS Res Hum Retroviruses ; 36(3): 205-213, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564109

RESUMO

Our primary objective was to assess the independent association between liver fibrosis (LF) and abdominal fat accumulation (AFA) and fatty liver disease (FLD). We also aimed to determine the diagnostic accuracy of AFA and FLD for the prediction of cirrhosis measured using unenhanced low-dose computed tomography (CT). This is a cross-sectional study in stable human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients with active HCV replication. CT was used to quantify fat content in segments III and VI of the liver and AFA. Transient elastometry was used to stage LF. Multivariate logistic regression, receiver operating characteristic curve analysis, and linear mixed model analysis were applied. One hundred fifteen HIV/HCV-coinfected patients were included. Cirrhosis was detected in 20.8% (24 patients). There was a high correlation between anthropometric characteristics and radiological variables. The factors independently associated with cirrhosis were albumin concentration [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.58-0.83; p < .0001] and visceral fat accumulation (OR, 1.02; 95% CI, 1.01-1.04; p = .0003). Multinomial analysis showed that visceral fat area (VFA) was the factor independently associated with stage F2 (OR, 1.02; 95% CI, 1.0-1.03; p < .005) and albumin concentration with stage F3 (OR, 0.75; 95% CI, 0.64-0.89; p < .001). VFA was the only radiological variable with an area under the curve >0.7 for the prediction of cirrhosis. There was no inter- or intraobserver variability in the measurement of AFA; however, high interobserver variability was recorded in the measurement of FLD. The association of VFA with cirrhosis, the high reproducibility of CT for the measurement of VFA, and the ability of VFA to predict cirrhosis make CT a suitable technique for identifying HIV/HCV-coinfected patients for closer surveillance.

9.
EClinicalMedicine ; 11: 65-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312806

RESUMO

Background: Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods: BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T-cells associated HIV-1 DNA. (NCT01712425). Findings: No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms. Interpretation: Heterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocused pre-cART T-cell responses towards more protective epitopes, in which immune escape is frequently associated with reduced HIV-1 replicative fitness and which are common to most global HIV-1 variants. Funding: HIVACAT Catalan research program for an HIV vaccine and Fundació Gloria Soler. Vaccine manufacture was jointly funded by the Medical Research Council (MRC) UK and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (G0701669. Research in Context: Evidence Before this Study: T cells play an important role in the control of HIV infection and may be particularly useful for HIV-1 cure by killing cells with reactivated HIV-1. Evidence is emerging that not all T-cell responses are protective and mainly only those targeting conserved regions of HIV-1 proteins are effective, but typically immunologically subdominant, while those recognizing hypervariable, easy-to-escape immunodominant 'decoys' do not control viremia and do not protect from a loss of CD4 T cells. We pioneered a vaccine strategy focusing T-cell responses on the most conserved regions of the HIV-1 proteome using an immunogen designated HIVconsv. T cells elicited by the HIVconsv vaccines in HIV-uninfected UK and Kenyan adults inhibited in vitro replication of HIV-1 isolates from 4 major global clades A, B, C and D.Added Value of this Study: The present study demonstrated the concept that epitopes subdominant in natural infection, when taken out of the context of the whole HIV-1 proteome and presented to the immune system by a potent simian adenovirus prime-poxvirus MVA boost regimen, can induce strong responses in patients on antiretroviral treatment and efficiently refocus HIV-1-specific T-cells to the protective epitopes delivered by the vaccine.Implications of all the Available Evidence: Nearly all HIV-1 vaccine strategies currently emphasize induction of broadly neutralizing Abs. The HIVconsv vaccine is one of a very few approaches focussing exclusively on elicitation of T cells and, therefore, can complement antibody induction for better prevention and cure. Given the cross-clade reach on the HIVconsv immunogen design, if efficient, the HIVconsv vaccines could be deployed globally. Effective vaccines will likely be a necessary component in combination with other available preventive measures for halting the HIV-1/AIDS epidemic.

10.
AIDS Res Hum Retroviruses ; 35(6): 513-518, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30909716

RESUMO

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Ritonavir/uso terapêutico , Adulto , Feminino , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , RNA Viral/sangue , Estudos Retrospectivos , Falha de Tratamento , Carga Viral/efeitos dos fármacos
11.
Rev. adm. pública (Online) ; 53(1): 45-63, Jan.-Feb. 2019. tab
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-990503

RESUMO

Resumen Los estudios de innovación en la actualidad no toman en cuenta o tienden a ignorar la innovación en las empresas públicas (EP) y sus efectos sobre otras organizaciones. Evidencia reciente muestra que las EP no son necesariamente inferiores a sus contrapartes privadas (Kowalski, Büge, Sztajerowska, & Egeland, 2013). Este trabajo investiga por primera vez mediante un estudio empírico los determinantes de la innovación en las EP de Ecuador. Identifica determinantes internos y externos de la innovación y su efecto en la probabilidad de innovación en EP. Además, se incluye la variable cuidado ambiental como determinante interno; esta variable no ha sido analizada en trabajos previos sobre innovación en EP. Los datos utilizados provienen de la encuesta de actividades de ciencia y tecnología e innovación de Ecuador (ACTI) publicada en el 2014. El modelo propuesto se estima mediante una regresión lineal de tipo logit. Los resultados muestran que existen determinantes que tienen efecto positivo sobre la probabilidad de innovación y que son de dos tipos: internos (trabajadores, capacitación, adquisición de tecnología y cuidado ambiental) y externos (gobierno, mediante el programa de apoyo a la gestión de calidad).


Resumo Os estudos de inovação atualmente não levam em conta e tendem a ignorar a inovação nas empresas públicas (EP) e seus efeitos sobre outras organizações. Evidências recentes mostram que as EP não são necessariamente inferiores às empresas privadas (Kowalski et al., 2013). Este artigo investiga pela primeira vez através de um estudo empírico os determinantes da inovação em EP no Equador. Identifica os determinantes internos e externos da inovação e seu efeito sobre a probabilidade de inovação no EP. Além disso, a variável cuidado ambiental é incluída como um determinante interno; esta variável não foi analisada em estudos anteriores sobre a inovação em EP. Os dados são da pesquisa de atividades de ciência, tecnologia e inovação do Equador (ACTI), publicado em 2014. O modelo proposto é avaliado por meio de uma regressão linear de tipo logit. Os resultados mostram que existem determinantes que têm efeito positivo sobre a probabilidade de inovação e são de dois tipos: internos (funcionários, treinamento, aquisição de tecnologia e cuidado ambiental) e externos (governo, mediante o apoio para gestão de qualidade).


Abstract The current studies on innovation do not consider or tend to ignore innovation in Public Enterprises (PE) and their effects on other organizations. Recent evidence shows that PE are not necessarily inferior to their private counterparts (Kowalski, Büge, Sztajerowska, & Egeland, 2013). This article investigates the determinants of innovation in PE of Ecuador, for the first time, through an empirical study. It identifies internal and external determinants of innovation and the effect on the probability of innovation in PE. In addition, the variable environmental care is included as an internal determinant; this variable has not been analyzed in previous work on innovation in PE. The data used come from the Survey of Activities of Science, Technology, and Innovation of Ecuador (ACTI) published in 2014. The proposed model is estimated by logit linear regression. The results show that there are determinants that have a positive effect on the probability of innovation and they are of two types: internal (workers training, technology acquisition and environmental care) and external (government, through the support program for quality management).

12.
J Assoc Nurses AIDS Care ; 30(1): 35-41, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30586082

RESUMO

The NEUrocognitive (NEU) Screen is a practical tool proposed to screen for HIV-associated cognitive impairment in the clinical setting. This is a pencil-and-paper method that can be applied rapidly (≤10 minutes for administration) and has no copyright limitations. In this study, we aimed at investigating its diagnostic accuracy in an older population of persons living with HIV (PLWH), with cutoffs set at 30, 40, 50, and 60 years. Data were collected from a sample of 368 PLWH who underwent a comprehensive neuropsychological tests battery (gold standard). Results of statistical tests showed that accuracy of the NEU Screen increased with age of the participants. The highest degree of precision, with a sensitivity of 91% and specificity of 92%, was obtained for people ages 60 years or older (correct classification: 91%). These optimal results point to the great potential of the NEU Screen as a tool for detecting cognitive disorders in older PLWH.


Assuntos
Transtornos Cognitivos/diagnóstico , Disfunção Cognitiva/diagnóstico , Infecções por HIV/complicações , Testes Neuropsicológicos/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Autorrelato , Sensibilidade e Especificidade , Espanha/epidemiologia
13.
Nutrients ; 10(7)2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29933630

RESUMO

Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, with dermatitis herpetiformis (DH) being the best characterized. These associated conditions may be the clue to reaching the diagnosis of CD. Over the last few years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in the absence of gastrointestinal symptoms, should give rise to an appropriate screening method for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated with CD and the possible mechanisms involved.


Assuntos
Doença Celíaca/diagnóstico , Membrana Mucosa/patologia , Dermatopatias/diagnóstico , Pele/patologia , Alopecia em Áreas/complicações , Alopecia em Áreas/diagnóstico , Doença Celíaca/complicações , Dermatite Herpetiforme/complicações , Dermatite Herpetiforme/diagnóstico , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Dieta Livre de Glúten , Gastroenteropatias/complicações , Gastroenteropatias/diagnóstico , Glutens/administração & dosagem , Humanos , Psoríase/complicações , Psoríase/diagnóstico , Rosácea/complicações , Rosácea/diagnóstico , Dermatopatias/complicações , Estomatite Aftosa/complicações , Estomatite Aftosa/diagnóstico , Urticária/complicações , Urticária/diagnóstico , Vasculite Leucocitoclástica Cutânea/complicações , Vasculite Leucocitoclástica Cutânea/diagnóstico
14.
J Antimicrob Chemother ; 73(9): 2452-2459, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860519

RESUMO

Background: Osteoporotic fractures still remain very infrequent and physicians rarely evaluate bone health. We wanted to assess the magnitude of this problem in the near future by determining the risk and likelihood of progression to osteoporosis. Methods: We estimated the risk of progression to osteopenia/osteoporosis among HIV-infected patients with at least 2 DXA scans (3726 scans from 875 patients). Time-non-homogeneous bidirectional multistate models based on three states (normal bone mineral density, osteopenia and osteoporosis) were used to model the progression of bone mineral density as a function of age and to study the association between the risk of bone loss and antiretroviral use. Results: The HRs associated with age (>45 versus ≤45 years) were: (i) from normal bone mineral density to osteopenia, 0.71 (95% CI 0.45-1.11) for men and 1.06 (95% CI 0.55-2.05) for women; and (ii) from osteopenia to osteoporosis, 0.83 (95% CI 0.51-1.35) for men and 0.99 (95% CI 0.38-2.56) for women. The transition probabilities from osteopenia to osteoporosis over 10 years among men aged 30 and 50 years were 14.9% (95% CI 10.5%-20.4%) and 19% (95% CI 14.3%-24.3%), respectively; and for women, 6.9% (95% CI 3.1%-14.4%) and 30.1% (95% CI 19.8%-41.8%), respectively. An increased osteoporosis risk was observed for PIs and PIs + tenofovir disoproxil fumarate; darunavir was associated with a higher risk of osteoporosis among men (HR 3.9; 95% CI 2-7.5) and women (HR 4.5; 95% CI 1.4-14.7); and atazanavir was associated with a higher risk of osteoporosis among women (HR 4.2; 95% CI 1.3-14). Conclusions: Our results highlight the importance of monitoring bone mineral density given the high probability of progression to osteopenia/osteoporosis, especially in women. In the future, changes in antiretrovirals other than tenofovir, such as PIs, should be recommended to reduce the risk of fracture.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Osteoporose/induzido quimicamente , Osteoporose/epidemiologia , Absorciometria de Fóton , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Feminino , Inibidores da Protease de HIV/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais
15.
Cancer Med ; 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29766673

RESUMO

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined  = 5.66 × 10-5 ; ORcombined  = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined  = 1.02 × 10-4 ; ORcombined  = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.

16.
Nutrients ; 10(5)2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735930

RESUMO

The Gilles de la Tourette syndrome (GTS) and Non-Coeliac Gluten Sensitivity (NCGS) may be associated. We analyse the efficacy of a gluten-free diet (GFD) in 29 patients with GTS (23 children; six adults) in a prospective pilot study. All of them followed a GFD for one year. The Yale Global Tics Severity Scale (YGTSS), the Yale-Brown Obsessive-Compulsive Scale—Self Report (Y-BOCS) or the Children’s Yale-Brown Obsessive-Compulsive Scale—Self Report (CY-BOCS), and the Cavanna’s Quality of Life Questionnaire applied to GTS (GTS-QOL) were compared before and after the GFD; 74% of children and 50% of adults were males, not significant (NS). At the beginning of the study, 69% of children and 100% of adults had associated obsessive-compulsive disorder (OCD) (NS). At baseline, the YGTSS scores were 55.0 ± 17.5 (children) and 55.8 ± 19.8 (adults) (NS), the Y-BOCS/CY-BOCS scores were 15.3, (standard deviation (SD) = 12.3) (children) and 26.8 (9.2) (adults) (p = 0.043), and the GTS-QOL scores were 42.8 ± 18.5 (children) and 64 ± 7.9 (adults) (p = 0.000). NCGS was frequent in both groups, with headaches reported by 47.0% of children and 83.6% of adults (p = 0.001). After one year on a GFD there was a marked reduction in measures of tics (YGTSS) (p = 0.001), and the intensity and frequency of OCD (Y-BOCS/CY-BOCS) (p = 0.001), along with improved generic quality of life (p = 0.001) in children and adults. In conclusion, a GFD maintained for one year in GTS patients led to a marked reduction in tics and OCD both in children and adults.


Assuntos
Dieta Livre de Glúten , Síndrome de Tourette/dietoterapia , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/dietoterapia , Cooperação do Paciente , Projetos Piloto , Gravidez , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Tiques/diagnóstico , Tiques/dietoterapia , Adulto Jovem
17.
J Ultrasound Med ; 37(1): 113-121, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28715086

RESUMO

OBJECTIVES: Liver fibrosis (LF) is crucial for the individualized management of patients with hepatitis C virus (HCV). We evaluated the concordance between two noninvasive methods for staging LF, transient elastography (TE) and acoustic radiation force impulse (ARFI), in patients coinfected with human immunodeficiency virus and HCV. We propose an algorithm for optimal use of both techniques in routine clinical practice. METHODS: A total of 89 human immunodeficiency virus/HCV-coinfected patients underwent TE and ARFI on the same day. The kappa index was used to assess concordance between the techniques. An algorithm combining ARFI and TE was proposed based on the independent factors associated with a kappa index greater than or equal to 0.70, obtained from a multiple regression analysis. We performed a cost-effectiveness analysis. The study was approved by our institutional review board and all patients signed the informed consent. RESULTS: Concordance between TE and ARFI for F2, F3, and F4 was 0.55, 0.59, and 0.69, respectively. Ultrasound normal spleen size (odds ratio [OR], 0.20; 95% confidence interval [CI], 0.05-0.91) and high viral load (OR, 0.36; 95% CI, 0.17-0.77) reduced the probability of agreement between TE and ARFI, whereas ultrasound normal left liver lobe size (OR, 3.32; 95% CI, 1.21-9.10) increased this probability. The algorithm revealed that LF was adequately assessed in 74.16%, with 25.84% of patients misclassified. The incremental cost-effectiveness ratio of TE compared with ARFI to increase concordance by 1% was €8.86. CONCLUSIONS: Concordance between TE and ARFI was moderate. In the algorithm we proposed, ARFI was cost-effective as a first technique for the staging of LF in the study population.


Assuntos
Coinfecção/complicações , Técnicas de Imagem por Elasticidade/métodos , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Coinfecção/diagnóstico por imagem , Feminino , Infecções por HIV/diagnóstico por imagem , Hepatite C Crônica/diagnóstico por imagem , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
18.
Medicine (Baltimore) ; 96(37): e7421, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28906351

RESUMO

Prevalence of kidney disease (KD) is increasing among human immunodeficiency virus (HIV)-infected population. Different factors have been related, varying on different published series.The objectives were to study prevalence of KD in those patients, its evolution, and associated risk factors.An observational cohort study of 1596 HIV-positive patients with cross-sectional data collection in 2008 and 2010 was conducted. We obtained clinical and laboratory markers, and registered previous or current treatment with tenofovir (TDF) and indinavir (IDV). The sample was divided according to estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) equation. Group 1: eGFR ≤60 mL/min/1.73 m; group 2: eGFR >60 mL/min/1.73 m.Among the patients, 76.4% were men, mean age (SD) 45 ±â€Š9 years, time since diagnose of HIV 14 ±â€Š7 years, and 47.2% of the patients received previous treatment with TDF and 39.1% with IDV. In 2008, eGFR ≤60: 4.9% (91.4% of them in chronic kidney disease [CKD] stage 3, eGFR 59-30 mL/min); this group was older, presented higher fibrinogen levels, and more patients were treated previously with TDF and IDV. In 2010, eGFR ≤60: 3.9% (87.1% stage 3 CKD). The 2.4% of cohort showed renal improvement and 1.3% decline of renal function over time. The absence of hypertension and treatment with TDF were associated with improvement in eGFR. Increased age, elevated fibrinogen, decreased albumin, diabetes mellitus, hyperTG, and worse virological control were risk factors for renal impairment.The HIV-positive patients in our area have a CKD prevalence of 4% to 5% (90% stage 3 CKD) associated with ageing, inflammation, worse immune control of HIV, TDF treatment, and metabolic syndrome.


Assuntos
Infecções por HIV/epidemiologia , Nefropatias/epidemiologia , Animais , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Nefropatias/complicações , Nefropatias/metabolismo , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Fatores de Risco , Espanha/epidemiologia
19.
PLoS One ; 12(9): e0184929, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28953921

RESUMO

The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/fisiologia , Vacinação , DNA Viral/metabolismo , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Imunidade Humoral , Resultado do Tratamento , Carga Viral/imunologia
20.
PLoS One ; 12(8): e0182547, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28854283

RESUMO

OBJECTIVE: To assess the efficacy and safety of transdermal rivastigmine for the treatment of HIV-associated cognitive impairment. METHODS: We recruited HIV-infected patients with cognitive impairment on stable antiretroviral therapy in a randomized controlled pilot trial with a 48-week follow-up. An additional assessment was held at 12 weeks. Participants received transdermal rivastigmine (9.5 mg daily), lithium (400 mg twice daily, titrated progressively), or remained in a control group (no new medication). The primary efficacy endpoint was change in a global cognitive score (NPZ-7). Secondary endpoints included change in specific cognitive measures, domains, and functional parameters. Safety covered the frequency of adverse events and changes in laboratory results. RESULTS: Seventy-six subjects were screened, and 29 were finally enrolled. Better cognitive outcomes were observed in all groups, although there were no significant differences between the arms (mean NPZ-7 change [SD]): rivastigmine, 0.35 (0.14); lithium, 0.25 (0.40); control, 0.20 (0.44) (p = 0.78). The rivastigmine group showed the highest positive trend (mean NPZ-7 [SD], baseline vs week 48): rivastigmine, -0.47 (0.22) vs -0.11 (0.29), p = 0.06; lithium, -0.50 (0.40) vs -0.26 (0.21), p = 0.22; control, -0.52 (0.34) vs -0.32 (0.52), p = 0.44. The cognitive domains with the highest positive trends were information processing speed at week 12 and executive function at week 48 (rivastigmine vs control): information processing speed, 0.35 (0.64) vs -0.13 (0.25), p = 0.17, d = 0.96; and executive functioning, 0.73 (0.33) vs 0.03 (0.74), p = 0.09, d = 1.18. No relevant changes were observed regarding functional outcomes. A total of 12 (41%) individuals dropped out of the study: 2 (20%) were due to medication-related effects in the rivastigmine group and 4 (36%) in the lithium group. No severe adverse events were reported. CONCLUSIONS: The results from this small randomized trial indicate that transdermal rivastigmine did not provide significant cognitive benefits in people with HAND on stable antiretroviral therapy, even though positive trends were found in specific cognitive domains. Relevant tolerability issues were not observed.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Infecções por HIV/complicações , Fármacos Neuroprotetores/uso terapêutico , Rivastigmina/uso terapêutico , Administração Cutânea , Adulto , Antirretrovirais/uso terapêutico , Disfunção Cognitiva/virologia , Função Executiva/efeitos dos fármacos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Testes Neuropsicológicos , Projetos Piloto , Rivastigmina/administração & dosagem , Rivastigmina/efeitos adversos , Resultado do Tratamento
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