Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic ...dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.
Objectives The EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study (HRS) assessed the safety and effectiveness of the MitraClip device (Abbott Vascular, Santa Clara, California) in ...patients with significant mitral regurgitation (MR) at high risk of surgical mortality rate. Background Patients with severe MR (3 to 4+) at high risk of surgery may benefit from percutaneous mitral leaflet repair, a potentially safer approach to reduce MR. Methods Patients with severe symptomatic MR and an estimated surgical mortality rate of ≥12% were enrolled. A comparator group of patients screened concurrently but not enrolled were identified retrospectively and consented to compare survival in patients treated by standard care. Results Seventy-eight patients underwent the MitraClip procedure. Their mean age was 77 years, >50% had previous cardiac surgery, and 46 had functional MR and 32 degenerative MR. MitraClip devices were successfully placed in 96% of patients. Protocol-predicted surgical mortality rate in the HRS and concurrent comparator group was 18.2% and 17.4%, respectively, and Society of Thoracic Surgeons calculator estimated mortality rate was 14.2% and 14.9%, respectively. The 30-day procedure-related mortality rate was 7.7% in the HRS and 8.3% in the comparator group (p = NS). The 12-month survival rate was 76% in the HRS and 55% in the concurrent comparator group (p = 0.047). In surviving patients with matched baseline and 12-month data, 78% had an MR grade of ≤2+. Left ventricular end-diastolic volume improved from 172 ml to 140 ml and end-systolic volume improved from 82 ml to 73 ml (both p = 0.001). New York Heart Association functional class improved from III/IV at baseline in 89% to class I/II in 74% (p < 0.0001). Quality of life was improved (Short Form-36 physical component score increased from 32.1 to 36.1 p = 0.014 and the mental component score from 45.5 to 48.7 p = 0.065) at 12 months. The annual rate of hospitalization for congestive heart failure in surviving patients with matched data decreased from 0.59 to 0.32 (p = 0.034). Conclusions The MitraClip device reduced MR in a majority of patients deemed at high risk of surgery, resulting in improvement in clinical symptoms and significant left ventricular reverse remodeling over 12 months. (Pivotal Study of a Percutaneous Mitral Valve Repair System EVEREST II; NCT00209274 )
Objectives This study sought to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. Background Transcatheter therapies are being developed to treat valvular heart ...disease. In the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II trial, treatment of mitral valve regurgitation (MR) with a novel percutaneous device was compared with surgery and showed superior safety, but less reduction in MR at 1 year overall. We report the 4-year outcomes from the EVEREST II trial. Methods Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip (Abbott, Menlo Park, California) device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. Results At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8% versus 53.4% in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4% versus 17.8% (p = 0.914), and 3+ or 4+ MR was present in 21.7% versus 24.7% (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4% versus 2.2% (p < 0.001) at 1 year and 24.8% versus 5.5% (p < 0.001) at 4 years. Conclusions Patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow-up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years. (Endovascular Valve Edge-to-Edge Repair Study EVEREST II; NCT00209274 )
Summary The NINCDS–ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of ...scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid β or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid β as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.
Abstract Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. ...Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic blood pressure readings ≥140 mmHg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic pressure ≤60 mmHg, especially in the presence of left ventricular hypertrophy. Following a hemorrhagic stroke, in the first 24 hours, systolic blood pressure lowering to <140 mmHg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.
Summary In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging–Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's ...disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
Background Long-acting muscarinic antagonist (LAMA)/long-acting β2 -agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a ...LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate GP/formoterol FF 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. Methods These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only open-label active comparator). Efficacy and safety were assessed. Results At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). Conclusions We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. Trial Registry ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658 ; URL: www.clinicaltrials.gov.
Abstract Background Bifurcation lesions are frequent among patients with symptomatic coronary disease treated by percutaneous coronary intervention. Current evidence recommends a conservative ...(provisional) approach when treating the side branch (SB). Objectives The TRYTON (Prospective, Single Blind, Randomized Controlled Study to Evaluate the Safety & Effectiveness of the Tryton Side Branch Stent Used With DES in Treatment of de Novo Bifurcation Lesions in the Main Branch & Side Branch in Native Coronaries) bifurcation trial sought to compare treatment of de novo true bifurcation lesions using a dedicated bifurcation stent or SB balloon angioplasty. Methods We randomly assigned patients with true bifurcation lesions to a main vessel stent plus provisional stenting or the bifurcation stent. The primary endpoint (powered for noninferiority) was target vessel failure (TVF) (cardiac death, target vessel myocardial infarction, and target vessel revascularization). The secondary angiographic endpoint (powered for superiority) was in-segment percent diameter stenosis of the SB at 9 months. Results We randomized 704 patients with bifurcation coronary lesions at 58 centers (30 from Europe and 28 from the United States). At 9 months, TVF was 17.4% in the bifurcation stent group compared with 12.8% in the provisional group (p = 0.11), mainly because of a higher periprocedural myocardial infarction rate (13.6% vs. 10.1%, p = 0.19). The TVF difference of +4.6% (2-sided 95% confidence interval: −1.0 to 10.3; upper limit of the 1-sided 95% confidence interval: 10.3) was not within the pre-specified noninferiority margin of 5.5% (p = 0.42 for noninferiority). The SB in-segment diameter stenosis among the angiographic cohort was lower in the bifurcation stent group compared with the provisional group (31.6% vs. 38.6%, p = 0.002 for superiority), with no difference in binary restenosis rates (diameter stenosis ≥50%) at 9 months follow-up (22.6% vs. 26.8%, p = 0.44). Conclusions Provisional stenting should remain the preferred strategy for treatment of non–left main true coronary bifurcation lesions. (Prospective, Single Blind, Randomized Controlled Study to Evaluate the Safety & Effectiveness of the Tryton Side Branch Stent Used With DES in Treatment of de Novo Bifurcation Lesions in the Main Branch & Side Branch in Native Coronaries TRYTON; NCT01258972 )
Summary Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, ...but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1–30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 106 CAR-transduced T cells per kg (dose 1), 3 × 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov , number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0–36·3). The most common non-haematological grade 3 adverse events were fever (nine 43% of 21 patients), hypokalaemia (nine 43% of 21 patients), fever and neutropenia (eight 38% of 21 patients), and cytokine release syndrome (three 14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.
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