Abstract Objective Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. ...However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable. Approach and results We tested the association of ADAM17 (A Disintegrin and Metallo Protease Domain 17) circulating substrates (sICAM-1, sVCAM-1, sIL6R and sTNFR1) with a second major cardiovascular events MACEs (cardiovascular death, peripheral artery surgeries, non-fatal myocardial infarction and non-fatal stroke) in 298 patients belonging to the Vascular Diabetes (AVD) study. To evaluate ADAM17 activity we create ADAM17 score through a RECPAM model. Finally we tested the discrimination ability and the reclassification of clinical models. At follow-up (mean 47 months, range 1–118 months), 55 MACEs occurred (14 nonfatal MI, 14 nonfatal strokes, 17 peripheral artery procedures and 10 cardiovascular deaths) (incidence = 7.8% person-years). An increased risk for incident events was observed among the high ADAM17 score individuals both in univariable (HR 19.20, 95% CI 15.82–63.36, p < 0.001) and multivariable analysis (HR 3.42, 95% CI 1.55–7.54, p < 0.001). Finally we found that ADAM17 score significantly increases the prediction accuracy of the Framingham Recurring - Coronary-Heart-Disease-Score , with a significant improvement in discrimination (integrated discrimination improvement = 9%, p = 0.012) and correctly reclassifying 10% of events and 41% of non-events resulting in a cNRI = 0.51 (p = 0.005). Conclusion We demonstrated a positive role of ADAM17 activity to predicting CV events. We think that an approach that targets strategies beyond classic cardiovascular risk factors control is necessary in individuals with an established vascular atherosclerosis.
Background Sexual dysfunction is an under-recognized problem in men and women with chronic kidney disease (CKD). The prevalence, correlates, and predictors of this condition in patients with CKD have ...not been evaluated comprehensively. Study Design Systematic review and meta-analysis. Setting & Population Patients treated using dialysis (dialysis patients), patients treated using transplant (transplant recipients), and patients with CKD not treated using dialysis or transplant (nondialysis nontransplant patients with CKD). Selection Criteria for Studies Observational studies conducted in patients with CKD only or including a control group without CKD. Predictor Type of study population. Outcomes Sexual dysfunction in men and women with CKD using validated tools, such as the International Index of Erectile Function, the Female Sexual Function Index (FSFI), or other measures as reported by study investigators. Results 50 studies (8,343 patients) of variable size (range, 16-1,023 patients) were included in this review. Almost all studies explored sexual dysfunction in men and specifically erectile dysfunction. The summary estimate of erectile dysfunction in men with CKD was 70% (95% CI, 62%-77%; 21 studies, 4,389 patients). Differences in reported prevalence rates of erectile dysfunction between different studies were attributable primarily to age, study populations, and type of study tool used to assess the presence of erectile dysfunction. In women, the reported prevalence of sexual dysfunction was assessed in only 306 patients from 2 studies and ranged from 30%-80%. Compared with the general population, women with CKD had a significantly lower overall FSFI score (8 studies or subgroups, 407 patients; mean difference, −9.28; 95% CI, −12.92 to −5.64). Increasing age, diabetes mellitus, and depression consistently were found to correlate with sexual dysfunction in 20 individual studies of patients with CKD using different methods. Limitations Suboptimal and lack of uniform assessment of outcome measures. Conclusions Sexual dysfunction is highly prevalent in both men and women with CKD, especially among those on dialysis. Larger studies enrolling different ethnic groups, using validated study tools, and analyzing the influence of various factors on the development of sexual dysfunction are needed.
Background Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. ...Study Design Prospective multinational cohort. Setting & Participants 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis ORAL-D Study). Predictors Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. Outcomes All-cause and cardiovascular mortality at 12 months after dental assessment. Measurements Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. Results During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score ≥ 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 95% CI, 0.32-0.85, 0.79 95% CI, 0.64-0.97, 0.76 95% CI, 0.58-0.99, 0.84 95% CI, 0.71-0.99, 0.79 95% CI, 0.65-0.95, and 0.79 95% CI, 0.65-0.96, respectively) were associated with better survival. Results for cardiovascular mortality were similar. Limitations Convenience sample of clinics. Conclusions In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival.
BACKGROUNDLittle information is available regarding hypertension, treatment, and control in urban population of Latin America.
OBJECTIVEWe aimed to compare blood pressure (BP) distribution, ...hypertension prevalence, treatment, and control in seven Latin American cities following standard methodology.
METHODSThe Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study was a cross-sectional, epidemiologic study assessing cardiovascular risk factors using stratified multistage sampling of adult populations (aged 25–64 years) in seven citiesBarquisimeto (Venezuela; n = 1848); Bogotá (n = 1553); Buenos Aires (n = 1482); Lima (n = 1652); Mexico City (n = 1720); Quito (n = 1638); and Santiago (n = 1655). The prevalence of hypertension and high normal BP were determined based on 2007 European Society of Hypertension and European Society of Cardiology definitions.
RESULTSBP increased with age in men and women; pulse pressure increased mainly in the upper age group. The hypertension prevalence ranged from 9% in Quito to 29% in Buenos Aires. One-quarter to one-half of the hypertension cases were previously undiagnosed (24% in Mexico City to 47% in Lima); uncontrolled hypertension ranged from 12% (Lima) to 41% (Mexico City). High normal BP was also evident in a substantial number of each city participants (≈5–15%). Majority of population has other cardiovascular risk factors despite hypertension; only 9.19% of participants have no risk factors apart from hypertension.
CONCLUSIONFrom 13.4 to 44.2% of the populations of seven major Latin American cities were hypertensive or had high normal BP values. Most hypertensive patients have additional risk factors. Public health programs need to target prevention, detection, treatment, and control of total cardiovascular risk in Latin America.
Comparative effectiveness research using real-world data often involves pairwise propensity score matching to adjust for confounding bias. We show that corresponding treatment effect estimates may ...have limited external validity, and propose two visualization tools to clarify the target estimand.
We conduct a simulation study to demonstrate, with bivariate ellipses and joy plots, that differences in covariate distributions across treatment groups may affect the external validity of treatment effect estimates. We showcase how these visualization tools can facilitate the interpretation of target estimands in a case study comparing the effectiveness of teriflunomide (TERI), dimethyl fumarate (DMF) and natalizumab (NAT) on manual dexterity in patients with multiple sclerosis.
In the simulation study, estimates of the treatment effect greatly differed depending on the target population. For example, when comparing treatment B with C, the estimated treatment effect (and respective standard error) varied from -0.27 (0.03) to -0.37 (0.04) in the type of patients initially receiving treatment B and C, respectively. Visualization of the matched samples revealed that covariate distributions vary for each comparison and cannot be used to target one common treatment effect for the three treatment comparisons. In the case study, the bivariate distribution of age and disease duration varied across the population of patients receiving TERI, DMF or NAT. Although results suggest that DMF and NAT improve manual dexterity at 1 year compared with TERI, the effectiveness of DMF versus NAT differs depending on which target estimand is used.
Visualization tools may help to clarify the target population in comparative effectiveness studies and resolve ambiguity about the interpretation of estimated treatment effects.
To evaluate the effect of natalizumab on disability progression beyond 2 years of treatment in clinical practice.
Analyses included the 496 relapsing-remitting multiple sclerosis (RRMS) patients ...among 5122 patients in the Tysabri Observational Program (TOP) who had completed 4 continuous years of natalizumab treatment and had baseline (study enrollment) and postbaseline Expanded Disability Status Scale (EDSS) assessments. Proportions of patients with 6-month or 12-month confirmed ≥1.0-point EDSS progression relative to baseline were compared in treatment months 1-24 and 25-48. Sensitivity analyses compared progression rates in months 13-24 and 25-36.
Baseline characteristics appeared similar between the overall TOP population (N = 5122), patients who had completed 4 years of natalizumab treatment (n = 469), and patients eligible to complete 4 years in TOP who had discontinued natalizumab after 2 years of treatment (n = 514). Among 4-year completers, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased between months 1-24 and 25-48 of natalizumab treatment by 42% (from 10.9% to 6.3%; p < 0.01) and 52% (from 9.5% to 4.6%; p < 0.01), respectively. Few patients had 6-month or 12-month confirmed EDSS progression in both epochs (0.6% and 0.2%, respectively). Between months 13-24 and 25-36 of treatment, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased by 60% (from 7.5% to 3.0%; p < 0.01) and 58% (from 6.7% to 2.8%; p < 0.01), respectively. Significant reductions in disability progression events between months 13-24 and 25-36 were also observed in relapse-free patients.
In this observational study, the disability progression rate decreased further beyond 2 years of natalizumab treatment. Patients who responded well and remained on continuous natalizumab therapy for over 4 years had sustained and potentially enhanced reductions in EDSS progression over time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms ...may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24-10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.
Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this ...study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.
Background
Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects fail to capture ...possible treatment effect heterogeneity. With the clinical course of the disease being highly heterogeneous across patients, precision medicine methods enable treatment response heterogeneity investigations.
Objective
To compare real-world effectiveness and discontinuation profiles between dimethyl fumarate and fingolimod while investigating treatment effect heterogeneity with precision medicine methods.
Methods
Adults initiating dimethyl fumarate or fingolimod as a second-line therapy were selected from a French registry. The primary outcome was annualized relapse rate at 12 months. Seven secondary outcomes relative to discontinuation and disease progression were considered. A precision medicine framework was used to characterize treatment effect heterogeneity.
Results
Annualized relapse rates at 12 months were similar for dimethyl fumarate and fingolimod. The odd of treatment persistence was 47% lower for patients treated with dimethyl fumarate relative to those treated with fingolimod (odds ratio: 0.53, 95% confidence interval: 0.39, 0.70). None of the five precision medicine scoring approaches identified treatment heterogeneity.
Conclusion
These findings substantiated the similar effectiveness and different discontinuation profiles for dimethyl fumarate and fingolimod as a second-line therapy for relapsing-remitting multiple sclerosis, with no significant effect heterogeneity observed.
Despite advances in clinical management of pancreatic cancer (PC), there is still room for improvement in early detection, diagnosis, and treatment strategies. The role of microRNAs (miRNAs) in tumor ...biology might pinpoint an alteration in expression of miRNAs as new diagnostic/prognostic biomarkers.
Expression levels of miR-143 and miR-21 and correlations with clinicopathological features were analyzed in 26 matched pairs of tumor and adjacent noncancerous tissue samples collected from patients with PCs, including 18 pancreatic ductal adenocarcinomas (PDACs) and 8 adenocarcinomas of Vater's papilla (PVACs).
Compared to normal tissues, miR-143 was up-regulated in both PDAC and PVAC tumor samples (P = 0.0028 and P = 0.039, respectively). Conversely, alterations in miR-21 expression were significantly different in PDAC versus PVAC samples (P = 0.0049). Tumor levels of miR-21 were associated with preoperative serum levels of CA 19-9 (r = 0.63, P = 0.0022), whereas miR-143 expression was negatively correlated to lymph node spreading (r = -0.64; P = 0.0004). Correlation between miR-143 and miR-21 expression levels in patients with PDAC was observed (r = 0.53, P = 0.023).
Deregulation of miR-143 and miR-21 may reflect histological features and biological behavior of different PCs. Association data with clinical parameters might indicate a prognostic significance for miR-143 and miR-21 in PCs.
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