Abstract While the proportion of patients with significant statin-associated adverse effects or intolerance is very low, the increasing use and broadening indications have led to a significant ...absolute number of such patients commonly referred to tertiary care facilities and specialists. This report provides a comprehensive overview of the evidence pertaining to a broad variety of statin-associated adverse effects followed by a consensus approach for the prevention, assessment, diagnosis, and management. The overview is intended both to provide clarification of the untoward effects of statins and to impart confidence in managing the most common issues in a fashion that avoids excessive ancillary testing and/or subspecialty referral except when truly necessary. The ultimate goal is to ensure that patients who warrant cardiovascular risk reduction can be treated optimally, safely, and confidently with statin medications or alternatives when warranted.
Adverse reactions to vaccines Kelso, John M; Li, James T; Nicklas, Richard A ...
Annals of allergy, asthma, & immunology,
10/2009, Letnik:
103, Številka:
4 Suppl 2
Journal Article
Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the ...large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response.
Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed.
No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation.
Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.
The incidence of aortic regurgitation (AR) after transcatheter aortic valve replacement (TAVR) in a self-expanding and a balloon-expandable system is controversial. This study aimed to examine the ...incidence and severity of post-TAVR AR with the CoreValve (CV) versus the Edwards XT Valve (XT). Baseline, procedural, and postprocedural inhospital outcomes were compared. The primary end point was the incidence of post-TAVR AR of any severity, assessed with a transthoracic echocardiogram, in the CV versus XT groups. A multivariate logistic regression analysis was completed to evaluate for correlates of the primary end point. The secondary end points included the change in severity of AR at 30-day and 1-year follow-up. A total of 223 consecutive patients (53% men, mean age 82 years) who had transfemoral TAVR with either a CV (n = 119) or XT (n = 104) were evaluated. The rates of post-TAVR AR in the groups were similar, and there was no evidence of more-than-moderate AR in either group. There were significant differences in the rates of intraprocedural balloon postdilation with the CV (17.1%) versus XT valve (5.8%; p = 0.009) and in the rates of intraprocedural implantation of a second valve-in-valve prosthesis with the CV (9.9%) versus XT valve (2.2%; p = 0.036). There were no significant differences in inhospital safety outcomes between the 2 groups. In conclusion, the incidence of post-TAVR AR is similar between the CV and the XT valve when performed by experienced operators using optimal intraprocedural strategies, as deemed appropriate, to mitigate the severity of AR.
Summary Background Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less ...effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori -associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy. Methods Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21–65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6–8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , registration number NCT01061437. Findings 1463 participants aged 21–65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82·2% (401 of 488), which was 8·6% higher (95% adjusted CI 2·6–14·5) than with concomitant therapy (73·6% 360 of 489) and 5·6% higher (–0·04% to 11·6) than with sequential therapy (76·5% 372 of 486). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites. Interpretation Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations. Funding Bill & Melinda Gates Foundation, US National Institutes of Health.
Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for surgical high-risk patients with severe aortic stenosis. The aim of this study was to determine the impact of ...atrial fibrillation (AF) on procedural outcomes. Data from 137 patients who underwent TAVR using Edwards SAPIEN valve were reviewed. The predictors of new-onset atrial fibrillation (NOAF) after the procedure were analyzed. In addition, the post-TAVR clinical outcomes and adverse events were compared according to the presence and absence of preprocedural and postprocedural AF. Previous AF was present in 49% of the patients who underwent TAVR. After the procedure, NOAF was detected in 21% of patients, and the cumulative incidence of post-TAVR AF was 60%. After TAVR, 50% of all the episodes of NOAF occurred in the initial 24 hours after the procedure. Transapical approach was observed to an important predictor of NOAF (adjusted odds ratio OR 5.05, 95% confidence interval CI 1.40 to 18.20, p = 0.013). The composite outcome of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after TAVR was significantly higher in patients with previous AF (33 of 67 vs 19 of 70, adjusted OR 2.60, 95% CI 1.22 to 5.54, p = 0.013) compared with patients who did not have previous AF. The presence of post-TAVR AF led to a prolongation in the duration of intensive care unit stay by an average of 70 hours (95% CI 25 to 114.7 hours, p = 0.002). Similarly, post-TAVR AF also led to the prolongation in the hospital stay by an average of 6.7 days (95% CI 4.69 to 8.73 days, p <0.0005). In conclusion, our study demonstrates that the presence of AF before TAVR is an important predictor of the composite end point of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after the procedure. AF after TAVR is more likely to be encountered with the transapical approach and is associated with a prolongation of intensive care unit and hospital stay.
Summary Background The progranulin gene ( GRN ) is mutated in 5–10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation ...in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. Methods We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene ( APOE ), and for haplotypes of the microtubule-associated protein tau gene ( MAPT ). Findings Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44–69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE ε4 allele. Interpretation Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.
The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain's energy consumption is ...devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the 'default' system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective Increased cardiovascular (CV) risk has been reported in adults who are childhood cancer survivors (CCS). We sought to determine the emergence of CV risk factors in CCS while still children. ...Study design CCS in remission ≥5 years from cancer diagnosis (n = 319, age = 14.5 years) and their siblings (control subjects, n = 208, age = 13.6 years) participated in this cross-sectional study of CV risk, which included physiologic assessment of insulin sensitivity/resistance (hyperinsulinemic euglycemic clamp). Adjusted comparisons between CCS major diagnoses (leukemia n = 110, central nervous system tumors n = 82, solid tumors n = 127) and control subjects were performed with linear regression for CV risk factors and insulin sensitivity. Results Despite no significant differences in weight and body mass index, CCS had greater adiposity (waist 73.1 versus 71.1 cm, P = .02; percent fat 28.1 versus 25.9%, P = .007), lower lean body mass (38.4 versus 39.9 kg, P = .01) than control subjects. After adjustment for adiposity, CCS had higher total cholesterol level (154.7 versus148.3 mg/dL, P = .004), low-density lipoprotein cholesterol level (89.4 versus 83.7 mg/dL, P = .002), and triglyceride level (91.8 versus 84 mg/dL, P = .03) and were less insulin sensitive (insulin stimulated glucose uptake, measure of insulin resistance, adjusted for lean body mass 12.1 versus 13.4 mg/kg/min, P = .002) than control subjects. Conclusions CCS have greater CV risk than healthy children. Because CV risk factors track from childhood to adulthood, early development of altered body composition and decreased insulin sensitivity in CCS may contribute significantly to their risk of early CV morbidity and mortality.
Objectives The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo) ...B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. Methods A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. Results The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema 90%) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations ≥3× the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Conclusions Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569 )
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