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Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin
Get PDFOBJECTIVES: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps
Lipidomics Reveals Reduced Inflammatory Lipid Species and Storage Lipids after Switching from EFV/FTC/TDF to RPV/FTC/TDF: A Randomized Open-Label Trial
Get PDFHIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients >/= 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA /=6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver((R)) Care and OWLiver((R)) tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4(+) count 740 cells/mm(3), TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log2 [fold-change] EFV vs. 0.059 log2 [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids
Sociotropy, Autonomy and Emotional Symptoms in Patients with Major Depression or Generalized Anxiety: The Mediating Role of Rumination and Immature Defenses
Get PDFThe relationships between dimensions of personality (sociotropy and autonomy), coping strategies (rumination: brooding and reflection subtypes, and immature defenses) and symptoms of depression and anxiety were explored in patients with Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD). A total of 279 patients completed questionnaires including measures of personality dimensions, rumination, immature defenses, depression and anxiety. Our findings suggested that sociotropy and autonomy may be associated with both depressive and anxious symptoms in patients with MDD and with GAD. Multiple mediation analyses indicated that brooding always acted as a mediating link between personality vulnerabilities (sociotropy and autonomy) and depressive and anxiety symptoms, independently of the patient group. In addition, in patients with MDD and those with GAD, brooding and immature defenses functioned together by linking sociotropy and autonomy, respectively, with depressive symptoms. Our results also showed that, in patients with GAD, both types of rumination explained the relationship between sociotropy and autonomy and anxiety symptoms. Overall, our findings provided evidence of the transdiagnostic role of the brooding, linking the vulnerability of personality dimensions and emotional symptoms. They also indicated that reflection and immature defenses can operate in conjunction with brooding, depending on the type of vulnerability and emotional context
Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis
Get PDFThe ability of Candida spp. to form biofilms is crucial for its pathogenicity, and thus, it should be considered an important virulence factor in vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC). Its ability to generate biofilms is multifactorial and is generally believed to depend on the site of infection, species and strain involved, and the microenvironment in which the infection develops. Therefore, both cell surface proteins, such as Hwp1, Als1, and Als2, and the cell wall-related protein, Sun41, play a critical role in the adhesion and virulence of the biofilm. Immunological and pharmacological approaches have identified the NLRP3 inflammasome as a crucial molecular factor contributing to host immunopathology. In this context, we have earlier shown that Candida albicans associated with hyphae-secreted aspartyl proteinases (specifically SAP4-6) contribute to the immunopathology of the disease. Transcriptome profiling has revealed that non-coding transcripts regulate protein synthesis post-transcriptionally, which is important for the growth of Candida spp. Other studies have employed RNA sequencing to identify differences in the 1,245 Candida genes involved in surface and invasive cellular metabolism regulation. In vitro systems allow the simultaneous processing of a large number of samples, making them an ideal screening technique for estimating various physicochemical parameters, testing the activity of antimicrobial agents, and analyzing genes involved in biofilm formation and regulation (in situ) in specific strains. Murine VVC models are used to study C. albicans infection, especially in trials of novel treatments and to understand the cause(s) for resistance to conventional therapeutics. This review on the clinical relevance of Candida biofilms in VVC focuses on important advances in its genomics, transcriptomics, and proteomics. Moreover, recent experiments on the influence of biofilm formation on VVC or RVVC pathogenesis in laboratory animals have been discussed. A clear elucidation of one of the pathogenesis mechanisms employed by Candida biofilms in vulvovaginal candidiasis and its applications in clinical practice represents the most significant contribution of this manuscript
Percutaneous mitral repair: current and future devices
Get PDFMitral regurgitation (MR) is the second most common valvular heart disease and its prevalence is increasing with population ageing. In the recent years we have witnessed the development of several transcatheter devices to correct MR in patients at high-risk for surgery. The majority of evidence regarding safety and efficacy of this new therapy comes from MitraClip studies. However, new alternatives on the field of valve repair have emerged with promising results. The aim of this review is to portrait the landscape of transcatheter mitral repair alternatives, from currently used devices to those that will have a role in the near future
Performance evaluation of deleteriousness prediction methods for intronic SNVs in next generation sequences
Get PDFIntroduction: Alterations in splicing sites (ss) are estimated to explain approximately 10% of human disease causal variants. Mutations outside the ss but affecting “regulatory elements” can be up to 25%. Accurate deleteriousness prediction for intronic variants is crucial for diagnostic purposes. Many deleteriousness prediction methods have been developed, but their relative values are still unclear in practical applications. We comprehensively evaluated the predictive performance of two complementary deleteriousness-scoring methods using information from real patients.
Material and Methods: We selected the dbscSNV (both ADA and RF scores) and SPIDEX algorithms, that study variants in splicing consensus regions or in regulatory regions respectively. The tools, either alone or in combination, were tested on 29294 gene intronic SNVs that have previously been characterised by ClinVar as either “pathogenic” (430) or “benign” (28864). The sensitivity, specificity and positive and negative predictive values were calculated. Moreover, we applied the algorithms to WES data from undiagnosed patients, and we analysed the mRNA sequence from genes that fitted the patient’s phenotype.
Results: The highest sensitivity corresponds to dbscSNV with 96.55% while the best specificity is for SPIDEX with 95.78%. When considering the 3 scores (SPIDEX, dbscSNV ADA and RF Score), the sensitivity and specificity values were 60.7% and 94.6%. The Positive and Negative Predictive Value were 14.45% and 99.39%. The results for 20 undiagnosed cases are presented.
Conclusions: Besides the low positive predictive value, the combination of both algorithms leads less than 1% of false negatives, so their routine use can be recommended for diagnostic purposes
Systematic Scoring Balloon Lesion Preparation for Drug-Coated Balloon Angioplasty in Clinical Routine: Results of the PASSWORD Observational Study
Get PDFINTRODUCTION: Scoring balloon angioplasty (SBA) for lumen gain prior to stent implantations or drug-coated balloon angioplasty (DCB) is considered an essential interventional tool for lesion preparation. Recent evidence indicates that SBA may play a pivotal role in enhancing the angiographic and clinical outcomes of DCB angioplasty. METHODS: We studied the systematic use of SBA with a low profile, non-slip element device prior to DCB angioplasty in an unselected, non-randomized patient population. This prospective, all-comers study enrolled patients with de novo lesions as well as in-stent restenotic lesions in bare metal stents (BMS-ISR) and drug-eluting stents (DES-ISR). The primary endpoint was the target lesion failure (TLF) rate at 9 months (ClinicalTrials.gov Identifier NCT02554292). RESULTS: A total of 481 patients (496 lesions) were recruited to treat de novo lesions (78.4%, 377), BMS-ISR (4.0%, 19), and DES-ISR (17.6%, 85). Overall risk factors were acute coronary syndrome (ACS, 20.6%, 99), diabetes mellitus (46.8%, 225), and atrial fibrillation (8.5%, 41). Average lesion lengths were 16.7 +/- 10.4 mm in the de novo group, and 20.1 +/- 8.9 mm (BMS-ISR) and 16.2 +/- 9.8 mm (DES-ISR) in the ISR groups. Scoring balloon diameters were 2.43 +/- 0.41 mm (de novo), 2.71 +/- 0.31 mm (BMS-ISR), and 2.92 +/- 0.42 mm (DES-ISR) whereas DCB diameters were 2.60 +/- 0.39 mm (de novo), 3.00 +/- 0.35 mm (BMS-ISR), and 3.10 +/- 0.43 mm (DES-ISR), respectively. The overall accumulated TLF rate of 3.0% (14/463) was driven by significantly higher target lesion revascularization rates in the BMS-ISR (5.3%, 1/19) and the DES-ISR group (6.0%, 5/84). In de novo lesions, the TLF rate was 1.1% (4/360) without differences between calcified and non-calcified lesions (p = 0.158) and small vs. large reference vessel diameters with a cutoff value of 3.0 mm (p = 0.901). CONCLUSIONS: The routine use of a non-slip element scoring balloon catheter to prepare lesions suitable for drug-coated balloon angioplasty is associated with high procedural success rates and low TLF rates in de novo lesions
Cost analysis of the management of brain metastases in patients with advanced ALK+ NSCLC: alectinib versus crizotinib
Get PDFAim: To estimate management cost of NSCLC ALK+ patients with and without brain metastasis (BM), and to compare annual costs in patients treated with alectinib or crizotinib. Methods: Management cost/year (euro 2018) in patients with and without BM was estimated with disaggregated resource consumption provided by local oncologists, including medical visits, hospitalizations, diagnostic/laboratory tests, imaging techniques and surgical procedures. The comparison of costs/year with alectinib and crizotinib, considered the cumulative 12-month incidence of BM in ALEX trial (9.4 and 41.4%, respectively). Results: Management cost was euro6173.42/patient-year without BM and euro21,637.50/patient-year with BM. With alectinib, average cost/patient was lower than crizotinib (euro4948.51/patient-year). Conclusion: Prevention of BM with alectinib may result in reductions of cost/year in the management of advanced ALK+ NSCLC
SEOM clinical guideline for treatment of kidney cancer (2019)
Get PDFIn this article, we review de state of the art on the management of renal cell carcinoma (RCC) and provide recommendations on diagnosis and treatment. Recent advances in molecular biology have allowed the subclassification of renal tumours into different histologic variants and may help to identify future prognostic and predictive factors. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. No adjuvant therapy has demonstrated a clear benefit in overall survival. Considering the whole population of patients with advanced disease, the combination of axitinib with either pembrolizumab or avelumab increase response rate and progression-free survival, compared to sunitinib, but a longer overall survival has only been demonstrated so far with the pembrolizumab combo. For patients with IMDC intermediate and poor prognosis, nephrectomy should not be considered mandatory. In this subpopulation, the combination of ipilimumab and nivolumab has also demonstrated a superior response rate and overall survival vs. sunitinib. In patients progressing to one or two antiangiogenic tyrosine-kinase inhibitors, both nivolumab and cabozantinib in monotherapy have shown benefit in overall survival compared to everolimus. Although no clear sequence can be recommended, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in patients with metastatic RCC
Looking into the genetic bases of OCD dimensions: a pilot genome-wide association study
Get PDFThe multidimensional nature of obsessive-compulsive disorder (OCD) has been consistently reported. Clinical and biological characteristics have been associated with OCD dimensions in different ways. Studies suggest the existence of specific genetic bases for the different OCD dimensions. In this study, we analyze the genomic markers, genes, gene ontology and biological pathways associated with the presence of aggressive/checking, symmetry/order, contamination/cleaning, hoarding, and sexual/religious symptoms, as assessed via the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS) in 399 probands. Logistic regression analyses were performed at the single-nucleotide polymorphism (SNP) level. Gene-based and enrichment analyses were carried out for common (SNPs) and rare variants. No SNP was associated with any dimension at a genome-wide level (p < 5 x 10(-8)). Gene-based analyses showed one gene to be associated with hoarding (SETD3, p = 1.89 x 10(-08)); a gene highly expressed in the brain and which plays a role in apoptotic processes and transcriptomic changes, and another gene associated with aggressive symptoms (CPE; p = 4.42 x 10(-6)), which is involved in neurotrophic functions and the synthesis of peptide hormones and neurotransmitters. Different pathways or biological processes were represented by genes associated with aggressive (zinc ion response and lipid metabolism), order (lipid metabolism), sexual/religious (G protein-mediated processes) and hoarding (metabolic processes and anion transport) symptoms after FDR correction; while no pathway was associated with contamination. Specific genomic bases were found for each dimension assessed, especially in the enrichment analyses. Further research with larger samples and different techniques, such as next-generation sequencing, are needed to better understand the differential genetics of OCD dimensions