Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practice

Non-metastatic castration-resistant prostate cancer (nmCRPC) represents a challenging disease state in prostate cancer care. nmCRPC patients with a high risk of progression to metastatic disease who are identified by a prostate-specific antigen doubling time (PSADT) ≤10 months are eligible for treatment with the novel androgen receptor inhibitors (ARIs), shown to delay disease progression and extend survival. However, nmCRPC is often unexploited in clinical practice due to a lack of standardization in the methodology and in the tools used for its identification. In this article, a group of Urology and Oncology specialists with acknowledged expertise in prostate cancer reviews the state of the art in the management of high-risk nmCRPC patients, identifies gaps and unmet needs, and proposes strategies to optimize the identification of this patient subgroup in the clinical practice and improve their health outcomes.info:eu-repo/semantics/publishedVersio

Pulse wave velocity and coronary risk stratification.

Introdução: A compliance arterial ou distensibilidade é uma determinante fundamental nas doenças cardiovasculares, apresentando grande interesse a sua medição não invasiva. A velocidade da onda de pulso (VOP) é usada, actualmente, como um índice de distensibilidade arterial. Objectivos: Avaliar se a VOP constitui um factor de risco, independente, para doença das artérias coronárias (DAC). Investigar se a determinação da mesma pode constituir uma ferramenta útil, na estratificação do risco cardiovascular, tanto nos indivíduos assintomáticos, como nos doentes com DAC População e Métodos: 811 indivíduos, 301 consecutivos com DAC, confirmada por coronário-angiografia, média de idade 53,7±10,0 anos e 510 assintomáticos, seleccionados das listas eleitorais, média de idade 46,1±10,0 anos. Os indivíduos assíntomáticos formavam o grupo A e eram subdivididos em A1 (grupo sem HTA, dislipidémia e ou diabetes) e A2 (grupo com HTA, dislipidémia, e ou diabetes). Os doentes coronários constituiam o grupo B, também sub dividido em B1 sem HTA, dislipidémia e ou diabetes e B2 com HTA, dislipidemia e ou diabetes. Os dados foram expressos em média ± desvio padrão (DP). O teste t de Student foi usado para comparar as variáveis contínuas e o c2 para comparar as variáveis categóricas. A força da correlação independente entre as variáveis contínuas foi avaliada segundo Pearson. Finalmente, foi efectuado um modelo de regressão logística (step by step) para avaliar quais as variáveis que se relacionavam de forma significativa e independente com a DAC. A análise estatística foi efectuada através do software SPSS for Windows, sendo o valor de p <0,05 considerado significativo. Resultados: Comparando os dois grupos, A1 e A2, no primeiro, a média da VOP foi significantemente mais baixa em relação ao A2. Comparando o grupo B1 e B2, também no grupo B1 a média da VOP é mais baixa. No grupo A1 a VOP correlacionou-se, segundo Pearson, com a idade, pressão arterial sistólica (PAS), diastólica e média, IMC, glicémia, colesterol total, LDL, relação CT/HDL, ApoB, triglicerídeos, ingestão de álcool, relação cintura/anca (C/A), e proteína C reactiva(as). A correlação foi inversa com o colesterol HDL. No grupo A2 a correlação da VOP foi positiva com a idade, PAS, PAM, PAD, glicémia, CT/ HDL e pressão do pulso (PP). No grupo B1 a correlação foi positiva e significante com a idade, PAS, PAM, PAD e PP. Foi inversa com a fracção de ejecção do VE. No grupo B2, foi positiva e significante com a idade, PAS, PAM, relação C/A, PP e homocisteína. Conclusão: A VOP foi sempre, quer nos indivíduos assintomáticos quer nos doentes coronários, mais elevada nos grupos com maior número de factores de risco. Esta constatação sugere influência cumulativa dos factores de risco, no processo de rigidez arterial. Correlacionou-se de forma positiva e significativa, com alguns dos factores de risco clássicos e alguns dos novos marcadores bioquímicos de risco. Após análise de regressão logística, manteve-se na equação de forma significativa, mostrando ser um factor de risco independente para DAC. Assim, a avaliação da distensibilidade arterial, através da medição da VOP, poderá representar um método simples, rápido e não invasivo, capaz de estratificar o risco de DAC, tanto nos indivíduos assintomáticos com nos doentes coronários.BACKGROUND: Arterial compliance or stiffness is an important determinant of cardiovascular disease and there is considerable interest in its noninvasive measurement. Pulse wave velocity (PWV) is widely used as an index of arterial stiffness. AIM: To determine whether PWV is useful for risk stratification in both healthy individuals and coronary patients. METHODS: Control subjects, n=510, aged 46.1 +/- 11 years, with no history of coronary disease, were selected from electoral rolls, and coronary patients, n=301, aged 53.7 +/- 10 years, were selected from hospital patients with a history of coronary artery disease (CAD) confirmed by coronary angiogram (at least 75% obstruction of one of the main coronary vessels). The asymptomatic subjects without CAD formed Group A, and were subdivided into A1 (without hypertension, dyslipidemia and/or diabetes) and A2 (with hypertension, dyslipidemia and/or diabetes). The coronary patients formed Group B, who were also subdivided into B1, without these classic risk factors, and B2 with hypertension, dyslipidemia and/or diabetes. We used the Student's t test to compare continuous variables and the chi-square test to compare categorical data. The strength of correlation between continuous variables was tested by Pearson's linear correlation. Independent variables predictive of CAD were determined by backward logistic regression analysis. The statistical analysis was performed using SPSS for Windows version 11.0 and data were expressed as means +/- SD; a p value of 0.05 was considered significant. RESULTS: Comparing the two groups A1 and A2, mean PWV was significantly lower in group A1. Comparing B1 and B2, mean PWV was also significantly lower in group B1. In group A1, PWV was significantly and positively correlated with age, body mass index, waist-to-hip ratio, alcohol consumption, total/HDL cholesterol ratio, systolic, diastolic and mean blood pressure (BP), blood glucose, apo B, triglycerides, and high-sensitivity C-reactive protein, unlike HDL which was inversely correlated (Pearson's coefficient). In group A2, PWV was significantly and positively correlated with age, alcohol consumption, total/HDL cholesterol ratio, systolic, diastolic and mean BP, blood glucose and pulse pressure (PP), but not HDL, which was inversely correlated with PWV. In group B1, PWV was only significantly and positively correlated with age, systolic, mean, and diastolic BP and PP, and presented a significant inverse correlation with ejection fraction. However, in the high-risk coronary population (group B2), there was a positive correlation with age, waist-to-hip ratio, systolic and mean BP, PP and homocysteine. After stepwise logistic regression, PWV remained in the model and proved to be a significant and independent risk factor for CAD. CONCLUSION: The results of our study show that PWV is higher in high-risk groups and significantly correlated with many classic and new CAD risk markers, suggesting that there is a cumulative influence of risk factors in the development of arterial stiffness. We believe that PWV is a useful index of vascular status and hence cardiovascular risk and that it may be useful for risk stratification in both asymptomatic and coronary patients.info:eu-repo/semantics/publishedVersio

Human Paraoxonase Gene Polymorphisms and Coronary Artery Disease Risk

Introdução: As doenças complexas como a doença das artérias coronárias (DAC), a hipertensão e a diabetes, são usualmente causadas pela susceptibilidade individual a múltiplos genes, factores ambientais e pela interacção entre eles. As enzimas da paraoxonase humana (PON), particularmente a PON1, têm sido implicadas na patogenia da aterosclerose e da DAC. Dois polimorfismos comuns na região codificante do gene, com substituição Glutamina (Q) /Arginina (R) na posição 192 e Leucina /Metionina na posição 55 influenciam a actividade da PON1. Vários estudos têm investigado a associação entre os polimorfismos da PON1 e a DAC, com resultados contraditórios. Objectivo: 1- Avaliar a associação dos polimorfismos da PON1 com o risco de DAC. 2-Estudar a interacção destes polimorfismos com outros situados em genes candidatos diferentes, na susceptibilidade para o aparecimento da DAC. Material e Métodos: Estudámos em 298 doentes coronários e 298 controlos saudáveis, através de um estudo caso/controlo, o risco de DAC associado aos polimorfismos da PON1, 192Q/R e 55L/M. Numa segunda fase avaliámos o risco das interacções polimórficas PON1 192 RR + MTHFR 1298 AA; PON1 192 R/R + ECA DD; PON1 192 R/R + ECA 8 GG. Finalmente construímos um modelo de regressão logística (no qual entraram todas as variáveis genéticas, ambientais e bioquímicas, que tinham mostrado significância estatística na análise univariada), para determinar quais as que se relacionavam de forma significativa e independente com DAC. Resultados: Verificámos que o genótipo PON155 MM tinha uma distribuição superior na população doente mas não atingia significância estatística como factor de risco para DAC. O PON1 199 RR apresentou um risco relativo 80% superior relativamente à população que o não possuía (p=0,04). A interacção da PON1 192 RR e da MTHFR 1298 AA, polimorfismos sedeados em genes diferentes, apresentou um risco relativo de DAC de 2,76 (OR=2,76;IC=1,20- 6,47; P=0,009), bastante superior ao risco de cada polimorfismo isolado, assim como a associação da PON1 RR + ECA DD (com polimorfismos também sedeados em genes diferentes), que apresentou um risco 337% superior relativamente aos que não possuíam esta associação (OR=4,37;IC=1,47- 13,87; P=0,002). Da mesma forma a associação entre a PON1 RR e ECA 8 GG, revelou um risco ainda mais elevado (OR=6;23; IC=1,67- 27,37; P<0,001). Após modelo de Regressão Logística as variáveis que ficaram na equação representando factores de risco significativos e independentes para DAC, foram os hábitos tabágicos, doença familiar, diabetes, fibrinogénio, Lp (a) e a associação PON1 192 RR + ECA 8 GG. Esta última associação apresentou, na regressão logística, um OR=14,113; p=0,018 Conclusões: O genótipo PON1 192 RR apresentou, se avaliado isoladamente, um risco relativo de DAC 80% superior relativamente à população que não possuía este genótipo. A associação deste polimorfismo com outros polimorfismos sedeados em genes diferentes, codificando para diferentes enzimas e pertencendo a sistemas fisiopatológicos distintos (MTHFR1298 AA, ECA DD e ECA 8 GG), aumentou sempre o risco de eclosão da DAC. Após correcção para os outros factores de risco clássicos e bioquímicos, a associação PON1 192 RR + ECA 8 GG, continuou a ser um factor de risco significativo e independente para CAD.Background: Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results. Aims: 1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes. Methods: We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD. Results: We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p<0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018. Conclusion: When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.info:eu-repo/semantics/publishedVersio

Polymorphism of the ACE Gene is Associated with Extent and Severity of Coronary Disease

Introdução: Os doentes com doença das artérias coronárias (DAC) apresentam extensão da doença e evolução muito variáveis, que muito vezes nos escapam e que ultrapassam os factores de risco tradicionais. As diferenças poderão, pelo menos em parte, ser explicáveis por polimorfismos genéticos menos favoráveis que lhe estejam associados. Os polimorfismos do gene da ECA têm sido profusamente avaliados, embora se desconheça a ligação entre estes polimorfismos e a extensão da DAC. Objectivo: Os autores pretendem avaliar se os polimorfismos do gene da enzima de conver são da Angiotensina I (ECA) constituem um marcador da extensão e gravidade da DAC. Métodos: Estudo descritivo, em 296 doentes com história de enfarte do miocárdio ou doença coronária confirmada por coronariografia, com pelo menos 75 % de obstrução de um dos vasos coronários. A quantificação da gravidade e extensão, foi feita segundo o score de Leaman, de acordo com o número de artérias com redução do diâmetro superior a 75 %, e com o número de segmentos coronários afectados. Os genotipos do ECA, foram tipados por amplificação por PCR e os produtos de amplificação separados por electroforese em gel de poliacrilamida. Calculou-se a média e desvio padrão dos scores coronários dos três polimorfismos e os valores foram comparados estatisticamente recorrendo ao teste T de Student para amostras independentes. Resultados e Conclusão: O genotipo DD aparece neste estudo claramente ligado à extensão da DAC, com um alto grau de significância. A confirmar-se este conceito, poderá justificar-se fazer uma prevenção secundária particularmente cuidadosa nos doentes vasculares portadores deste genotipo.Background: The progression and extent of coronary heart disease (CHD) are extremely variable and in many instances independent of conventional risk factors. The differences may be partly explained by less favorable genetic polymorphisms that are associated with them. The polymorphisms of the angiotensin I converting enzyme (ACE) gene have been thoroughly evaluated, but the connection between them and the extent of CHD is unknown. Aims: Our study is aimed at determining whether any or all of the polymorphisms of the ACE gene are markers of the extent and severity of CHD. Methods: This was a descriptive study of 296 patients with a history of myocardial infarction or with coronary disease confirmed by coronary angiography. The severity of CHD was quantified according to Leaman’s score (based on the number of arteries with more than 75 % reduction in diameter and the number of affected coronary segments). The ACE genotypes were determined by specific polymerase chain reaction amplification and the segments were subjected to polyacrylamide gel electrophoresis. The mean coronary score and standard deviation of the three polymorphisms were calculated and the values statistically compared using the Student’s t test for independent samples. Results: 296 patients with a mean age of 5510.3 years, 234 male, were evaluated. Conclusion: The study clearly shows that the DD genotype is linked to the extent of CHD, with a high level of significance. If this is confirmed, careful secondary prevention is indicated in patients with this genotype.info:eu-repo/semantics/publishedVersio

Angiotensin Converting Enzyme Gene Polymorphisms and Coronary Risk in a Portuguese Population

Introdução: A história familiar de doença das artérias coronárias (DAC) constitui um poderoso marcador de risco de DAC, independente dos factores de risco tradicionais. Poderá ser descodificado reconhecendo os polimorfismos associados ao aumento de risco. Têm surgido resultados contraditórios em relação à ligação entre os polimorfismos do gene da enzima de conver são da angiotensina (ECA) e o risco de DAC. Objectivo: Com o presente trabalho pretendemos avaliar se os polimorfismos do gene da ECA constituem factor de risco de doença das artérias coronárias. Métodos: Estudo caso-controlo, incluindo 517 controlos escolhidos aleatoriamente dos cadernos eleitorais, sem história sugestiva de DAC e 301 doentes com história de enfarte agudo do miocárdio ou doença coronária confirmada por coronariografia, com pelo menos 75 % de obstrução de um dos vasos coronários. Tentou-se que os casos e controlos não fossem significativamente diferentes em termos de sexo e idade. Os polimorfismos dialélicos do gene da ECA foram tipados por amplificação por PCR. Os produtos de amplificação eram identificados em gel de poliacrilamida, por electroforese. Os dados foram avaliados recorrendo ao SPSS for Windows,Background: A family history of coronary heart disease (CHD) is a strong risk marker for the disease, independently of classical risk factors. It could be decoded by recognizing the polymorphisms associated with increased risk. Renin-angiotensin system genes are candidate genes in CHD and the deletion allele of the angiotensin converting enzyme (ACE) has been reported as deleterious. However, there is disagreement as to the role of the insertion/deletion polymorphism of the ACE gene in coronary risk. Aim: To evaluate whether ACE gene polymorphisms constitute a CHD risk factor. Methods: We conducted a population-based case-control study of 301 subjects with a history of myocardial infarction or angiographic evidence of coronary heart disease and 510 age- and gender-matched controls, without CHD, living in a region with high CHD mortality rates. Blood samples were taken, DNA extracted and genotypes determined by the polymerase chain reaction (PCR). Amplification products were identified by agarose gel electrophoresis.info:eu-repo/semantics/publishedVersio

Simplified sewerage to prevent urban leptospirosis transmission: a cluster non-randomised controlled trial protocol in disadvantaged urban communities of Salvador, Brazil.

INTRODUCTION: Leptospirosis is a globally distributed zoonotic and environmentally mediated disease that has emerged as a major health problem in urban slums in developing countries. Its aetiological agent is bacteria of the genus Leptospira, which are mainly spread in the urine of infected rodents, especially in an environment where adequate sanitation facilities are lacking, and it is known that open sewers are key transmission sources of the disease. Therefore, we aim to evaluate the effectiveness of a simplified sewerage intervention in reducing the risk of exposure to contaminated environments and Leptospira infection and to characterise the transmission mechanisms involved. METHODS AND ANALYSIS: This matched quasi-experimental study design using non-randomised intervention and control clusters was designed to assess the effectiveness of an urban simplified sewerage intervention in the low-income communities of Salvador, Brazil. The intervention consists of household-level piped sewerage connections and community engagement and public involvement activities. A cohort of 1400 adult participants will be recruited and grouped into eight clusters consisting of four matched intervention-control pairs with approximately 175 individuals in each cluster in baseline. The primary outcome is the seroincidence of Leptospira infection assessed through five serological measurements: one preintervention (baseline) and four postintervention. As a secondary outcome, we will assess Leptospira load in soil, before and after the intervention. We will also assess Leptospira exposures before and after the intervention, through transmission modelling, accounting for residents' movement, contact with flooding, contaminated soil and water, and rat infestation, to examine whether and how routes of exposure for Leptospira change following the introduction of sanitation. ETHICS AND DISSEMINATION: This study protocol has been reviewed and approved by the ethics boards at the Federal University of Bahia and the Brazilian National Research Ethics Committee. Results will be disseminated through peer-reviewed publications and presentations to implementers, researchers and participating communities. TRIAL REGISTRATION NUMBER: Brazilian Clinical Trials Registry (RBR-8cjjpgm)

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Search for massive resonances in dijet systems containing jets tagged as W or Z boson decays in pp collisions at √s=8 TeV

Peer reviewe

Search for vector-like T quarks decaying to top quarks and Higgs bosons in the all-hadronic channel using jet substructure

Peer reviewe

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.