Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.

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Peripheral arterial disease (PAD) continues to grow in global prevalence and consumes an increasing amount of resources in the United States health care system. Overall rates of intervention for PAD have been rising steadily in recent years. Changing demographics, evolution of technologies, and an expanding database of outcomes studies are primary forces influencing clinical decision making in PAD. The management of PAD is multidisciplinary, involving primary care physicians and vascular specialists with varying expertise in diagnostic and treatment modalities. PAD represents a broad spectrum of disease from asymptomatic through severe limb ischemia. The Society for Vascular Surgery Lower Extremity Practice Guidelines committee reviewed the evidence supporting clinical care in the treatment of asymptomatic PAD and intermittent claudication (IC). The committee made specific practice recommendations using the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system. There are limited Level I data available for many of the critical questions in the field, demonstrating the urgent need for comparative effectiveness research in PAD. Emphasis is placed on risk factor modification, medical therapies, and broader use of exercise programs to improve cardiovascular health and functional performance. Screening for PAD appears of unproven benefit at present. Revascularization for IC is an appropriate therapy for selected patients with disabling symptoms, after a careful risk-benefit analysis. Treatment should be individualized based on comorbid conditions, degree of functional impairment, and anatomic factors. Invasive treatments for IC should provide predictable functional improvements with reasonable durability. A minimum threshold of a >50% likelihood of sustained efficacy for at least 2 years is suggested as a benchmark. Anatomic patency (freedom from restenosis) is considered a prerequisite for sustained efficacy of revascularization in IC. Endovascular approaches are favored for most candidates with aortoiliac disease and for selected patients with femoropopliteal disease in whom anatomic durability is expected to meet this minimum threshold. Conversely, caution is warranted in the use of interventions for IC in anatomic settings where durability is limited (extensive calcification, small-caliber arteries, diffuse infrainguinal disease, poor runoff). Surgical bypass may be a preferred strategy in good-risk patients with these disease patterns or in those with prior endovascular failures. Common femoral artery disease should be treated surgically, and saphenous vein is the preferred conduit for infrainguinal bypass grafting. Patients who undergo invasive treatments for IC should be monitored regularly in a surveillance program to record subjective improvements, assess risk factors, optimize compliance with cardioprotective medications, and monitor hemodynamic and patency status.