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INTRODUCTION — Aspirin-exacerbated respiratory disease (AERD), which is also called NSAID-exacerbated respiratory disease (NERD), refers to the combination of asthma, chronic rhinosinusitis (CRS) with nasal polyposis, and acute upper and lower respiratory tract reactions to ingestion of aspirin (acetylsalicylic acid, ASA) and other cyclooxygenase-1 (COX-1)-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs).
The first case of aspirin sensitivity in a patient with asthma was described in 1902, a few years after the introduction of aspirin into clinical use. In 1968, Samter and Beers described a triad consisting of asthma, aspirin sensitivity, and nasal polyps [1], which came to be known as Samter's triad.
An overview of AERD with emphasis on pathophysiology and the management of asthma will be presented here. Other types of hypersensitivity reactions to NSAIDs and the treatment of patients with asthma, CRS, and nasal polyposis are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Diagnostic challenge and desensitization protocols for NSAID reactions" and "An overview of asthma management" and "Chronic rhinosinusitis: Management".)
NSAIDs — The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (also called prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid (AA) to prostaglandins, prostacyclin, and thromboxanes and enhancing production of leukotrienes. Two related isoforms of the cyclooxygenase (COX) enzyme have been described, COX-1 and COX-2. Some NSAIDs have a greater inhibitory effect on COX-1 and others on COX-2. COX-1 inhibition is the stimulus for acute reactions to aspirin (ASA)/NSAIDs in aspirin-exacerbated respiratory disease (AERD).
In this topic review, the term "NSAID" includes aspirin (ASA). However, in some clearly marked sections, aspirin is discussed exclusive of other NSAIDs.
AERD — Aspirin-exacerbated respiratory disease (AERD) refers to the combination of:
●Chronic rhinosinusitis (CRS) with nasal polyposis
●Reactions to aspirin (acetylsalicylic acid, ASA) and other COX-1 inhibiting NSAIDs, in which symptoms of nasal congestion and bronchoconstriction typically begin 20 minutes to 3 hours after ingestion
Patients with AERD are also described as having aspirin-sensitive asthma or aspirin-intolerant asthma, although these terms refer to just one component of the disorder. The term "AERD" places emphasis on the chronic upper and lower respiratory disease as the fundamental disorder and a reaction to NSAIDs as an exacerbating factor [2,3]. In keeping with this, avoidance of NSAIDs by these patients does not result in resolution of asthma or CRS.
Pseudoallergy — Reactions to NSAIDs in patients with AERD are classified as "pseudoallergic" because they are not immunoglobulin E (IgE)-mediated. Pseudoallergic reactions are triggered by a wide range of structurally distinct medications that have in common the ability to inhibit the COX-1 enzyme. These reactions represent an abnormal biochemical response to the pharmacologic actions of NSAIDs. In contrast, IgE-mediated "allergic" reactions result from the formation of antibodies against a specific drug, haptenated drug, or a group of structurally similar drugs.
Reactions to aspirin in patients with AERD are characterized as type 1 pseudoallergic reactions. The other types of pseudoallergic reactions to NSAIDs are discussed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Pseudoallergic reactions'.)
PREVALENCE — The prevalence of aspirin-exacerbated respiratory disease (AERD) is approximately 7 percent among patients with asthma, based on a 2014 metaanalysis of clinical trial data [4]. Among patients with severe asthma, the prevalence is twice as high, at approximately 14 percent. Among patients with nasal polyposis or chronic rhinosinusitis, the prevalence is about 10 and 9 percent, respectively.
Nonsteroidal anti-inflammatory drug (NSAID) sensitivity is particularly prevalent in patients with both chronic rhinosinusitis (CRS) and nasal polyposis, and some patients may not be aware that they are sensitive to these medications. In a prospective study of 80 adults presenting consecutively to an allergy and immunology clinic with CRS and nasal polyps, 36 percent reported sensitivity to NSAIDs, but 49 percent reacted to aspirin upon challenge [5].
PATHOPHYSIOLOGY — The pathophysiology of aspirin-exacerbated respiratory disease (AERD) is not fully understood. There appears to be a dysregulation of arachidonic acid (AA) metabolism, particularly with an overproduction of leukotrienes, which may result from decreased inhibition of the 5-lipoxygenase (5-LO) pathway of AA metabolism by the prostaglandin E2 (PGE2). The overproduction of leukotrienes is further exacerbated by the action of cyclooxygenase-1 (COX-1) inhibitors (which block production of PGE2). In addition, patients with AERD may have decreased elaboration of downregulatory fatty acid products, such as lipoxins. Collectively, these abnormalities result in an imbalance between proinflammatory and anti-inflammatory mediators. AA metabolism, the role of mast cells, and other identified abnormalities in patients with AERD are reviewed in this section.
Normal arachidonic acid metabolism — AA is derived from the membrane phospholipids of many cell types and is metabolized along different pathways to yield various lipid mediators. Some of these mediators are proinflammatory and some are anti-inflammatory. A few can act in both capacities, depending upon the target cell. A simplified overview of AA metabolism is provided here.
5-lipoxygenase pathway — The metabolism of AA by the enzyme 5-LO generates the leukotrienes (LTs), as depicted in the figure (figure 1). The cysteinyl leukotrienes (cysLTs), LTC4, LTD4, and LTE4, are potent inducers of bronchoconstriction, mucus secretion, nasal mucosal swelling, and airway edema, and also attract eosinophils into the airways [6-8]. These are the major LTs synthesized by eosinophils and mast cells, cell types that are abundant in inflamed airways.
Leukotriene B4 (a non-cysLT) is also proinflammatory, but with effects on neutrophils and monocytes. Yet another 5-LO product, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), is a very potent eosinophil chemoattractant (figure 1).
Cyclooxygenase pathway — The metabolism of AA by the two cyclooxygenase isoforms (COX-1 and COX-2, also known as cycloendoperoxidase H synthases or prostaglandin synthases) yields prostaglandins and thromboxanes (figure 2) [9]. One of the prostaglandins, prostaglandin D2 (PGD2), is predominantly produced by mast cells and has a bronchoconstrictor effect. It appears to be overproduced at baseline in AERD and further increased after aspirin challenge [9-12]. Production of PGD2 and its metabolite, PGD2S, is relatively aspirin resistant and may be more dependent upon COX-2 than COX-1. In contrast, PGE2 is a bronchodilator with potent anti-inflammatory effects. It is expressed in a broad range of cells and is decreased after COX-1 inhibition [9,12,13]. PGE2 is believed to act as a "brake" on the production of the proinflammatory LTs. (See "NSAIDs: Pharmacology and mechanism of action".)
Abnormalities in AERD — Studies of AERD patients demonstrate a baseline dysregulation of AA metabolism with greatly increased production of the proinflammatory and underproduction of the anti-inflammatory products compared with non-AERD asthmatics [14-18]. The proinflammatory leukotrienes promote persistent airway inflammation. The baseline dysregulation is acutely exaggerated by ingestion of COX-1 inhibitors, perhaps because the synthesis of PGE2 is reduced and the "brake" on leukotrienes is released [19-22]. While mast cells have traditionally been thought to be the major source of cysLTs, accumulating evidence suggests that platelets may play a role in this process by providing the enzymes needed for leukocytes to produce leukotrienes [23,24].
The following abnormalities, which support this model of AERD pathophysiology, have been identified in patients with AERD [25-36]:
●The primary cellular source of leukotriene LTC4 in patients with AERD appears to be the bronchial mast cell, although eosinophils are also capable of producing large amounts [27]. Both cell types are increased and activated in the respiratory tracts of patients with AERD [28-30].
●The enzyme LTC4 synthase, which mediates the formation of LTC4, is overexpressed by eosinophils and other leukocytes in both nasal and pulmonary tissues of some patients with AERD (figure 1) [28,31].
●Abnormal aggregations of platelets and leukocytes (specifically, neutrophils, eosinophils, and monocytes) were demonstrated in nasal polyp tissue and peripheral blood from patients with AERD [23]. When closely associated, platelets and leukocytes can share metabolic processes (ie, transcellular synthesis) to produce enhanced amounts of proinflammatory leukotrienes. In patients with AERD, the percentages of platelet-leukocyte aggregates correlated with markers of systemic cysLT production, suggesting that these aggregates play a role in the enhanced production of leukotrienes.
●Leukocytes in the nasal mucosa of patients with AERD overexpress cysteinyl leukotriene receptor type 1, one of two known receptors for cysLTs (figure 3) [34].
●Medications that inhibit leukotriene synthesis or antagonize leukotriene receptors (eg, zileuton, montelukast) blunt or occasionally block the bronchoconstrictive response to aspirin [8,37-39].
●Levels of PGE2 in polyp tissue and lower airway fibroblasts of AERD patients are reduced at baseline and fall further after aspirin challenge [40-42]. PGE2 is believed to act as a brake on leukotriene production, as mentioned previously. The inhalation of PGE2 has been shown to prevent the reaction to inhaled forms of acetylsalicylic acid (ie, lysine-aspirin), as well as the rise in cysLTs [19], suggesting that altered PGE2 homeostasis may be key to this disorder. PGE2 suppresses leukotriene production through the activity of protein kinase A (PKA), and PKA activity was shown to be abnormally low in granulocytes in the blood of patients with AERD, compared with controls [43]. Additionally, several isoforms of the PGE receptors are reduced on the inflammatory cells in nasal polyp and bronchial tissues of AERD patients, further suggesting that altered PGE homeostasis may contribute to AERD [20,44].
●Additional evidence of a role for PGE2 in AERD comes from laboratory studies. PGE2-synthase-1 deficient mice demonstrate sustained increases in airway resistance, mast cell activation, and cysLT overproduction following inhalation of lysine-aspirin, similar to AERD in humans [45]. These effects were blocked by pretreatment with leukotriene antagonists.
Involvement of mast cells — Mast cells, especially those in the nasal and bronchial epithelium, may represent an important source of lipid mediators in patients with AERD. Evidence for mast cell activation and degranulation during aspirin challenge in patients with AERD includes demonstrable elevations in mast cell tryptase, histamine, and PGD2 [10,30]. In addition, H1 antihistamines may reduce the extent of nasal and ocular reactions to aspirin to varying degrees.
Other areas of investigation — Differences in complement proteins between asthmatics with and without aspirin sensitivity were revealed using proteomics [46]. A small case control study examined changes in expression of plasma proteins in six aspirin-sensitive and six aspirin-tolerant asthmatics at baseline and after aspirin challenge, compared with control patients without asthma. Baseline differences were detected in complement proteins, apolipoproteins, and albumin complexed with myristic acid, with significant up- and downregulation of these proteins after aspirin challenge. In particular, patients with AERD had higher levels of C3a and C4a than tolerant patients at baseline, with levels that correlated to changes in forced expiratory volume in one second (FEV1) during challenge.
CLINICAL PRESENTATION — Patients with aspirin-exacerbated respiratory disease (AERD) typically have chronic asthma and rhinosinusitis and experience acute exacerbations of upper and lower respiratory symptoms after the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). In a survey of 190 patients, the majority reported that AERD adversely affected their quality of life and identified chronic nasal symptoms and decreased sense of smell as important factors [47].
Temporal development of symptoms and signs — AERD is usually diagnosed in adulthood. Children and adolescents are rarely affected. The three component disorders of AERD tend to develop serially over a period of years [2,48], although some patients may present with rapid progression of sinonasal symptoms to asthma.
The majority of patients initially develop refractory rhinitis, which is usually established by their early 30s. This is followed by the development of chronic hypertrophic eosinophilic rhinosinusitis, characterized by nasal congestion, anosmia, and nasal polyposis (picture 1 and picture 2). Some patients report repeated sinus surgeries and polypectomies. On computed tomography (CT), mucosal thickening typically affects most, if not all, of the paranasal sinuses, and polyps may appear as rounded mucosal protrusions in the nasal or sinus cavities. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)
As the rhinosinusitis worsens, the patient typically develops inflammation in the lower airway and is diagnosed with asthma. At some point during this progression, aspirin/NSAID sensitivity appears. The asthma and chronic sinusitis of AERD usually become more severe over time, even with NSAID avoidance [3,49-51]. However, not all patients have severe asthma, and for many patients, the symptoms related to nasal polyposis and chronic rhinosinusitis (CRS) are more troubling on a day-to-day basis [2]. (See "Diagnosis of asthma in adolescents and adults".)
In rare cases, the NSAID sensitivity develops first, and NSAID intolerance is an independent risk factor for developing asthma [49-51].
Acute reactions to NSAIDs — Acute reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with AERD typically begin 30 minutes to 3 hours after NSAID ingestion, and may be slow to resolve (figure 4) [52]. The symptoms are dose related, ie, small doses of NSAIDs may produce minimal symptoms (such as isolated nasal congestion), whereas larger doses may induce severe bronchospasm requiring intubation. Fatal reactions have rarely occurred following full NSAID doses [2].
When patients with AERD are challenged with aspirin on an escalating dose schedule, most bronchoconstrictive reactions occur with low doses of 30 to 120 mg, while few patients require 325 mg or more [52]. Thus, when an unknowing patient with AERD ingests 650 mg of aspirin or its equivalent of ibuprofen (400 mg), naproxen (440 mg), or indomethacin (50 mg), reactions may be quite severe.
The classic reaction following NSAID ingestion consists of one or more of the following:
●Nasal and ocular symptoms, including nasal congestion/obstruction, watery rhinorrhea, periorbital edema, and/or injection of the conjunctiva – These symptoms are often the first manifestation of the reaction. However, patients may not recognize the association if the NSAID is taken at the time of an upper respiratory infection.
●Asthmatic symptoms, including wheezing, dyspnea, cough, and chest tightness – These symptoms are accompanied by a marked fall in forced expiratory volume in one second (FEV1). Bronchoconstriction is typically reversible with an inhaled beta-agonist bronchodilator.
Additional symptoms may occur in patients with severe respiratory reactions. These include facial flushing/erythema, laryngospasm, abdominal cramps, epigastric pain, and hypotension. Severe reactions may be difficult to distinguish from anaphylaxis.
Urticaria and/or angioedema occur in approximately 15 percent of AERD patients during these acute reactions. However, isolated urticaria and angioedema (without respiratory symptoms) are more characteristic of other distinct types of NSAID sensitivity without asthma, called NSAID-induced urticaria/angioedema (type 2 and 3 pseudoallergic reactions) (table 1). In addition, macular rashes have been noted during these reactions as well [12]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Pseudoallergic reactions'.)
Atopy and eosinophilia — Depending on the case series, between 30 and 70 percent of patients with AERD are atopic [2,53], and a portion of these patients have high levels of specific immunoglobulin E (IgE) antibodies to inhalant allergens [54,55]. Typically, perennial allergens such as dust mites are implicated [56]. However, total serum IgE levels are variable and do not tend to correlate with severity of sinus disease [57].
Peripheral blood eosinophilia is present in approximately 50 percent of AERD patients and appears to correlate with severity of CRS [57-60]. In a series of 81 AERD patients, 51 percent had peripheral blood eosinophilia [58].
Reactions to alcoholic beverages — Patients with AERD often report that alcoholic beverages induce symptoms in the upper (nasal congestion and rhinorrhea) and lower (wheezing, shortness of breath) respiratory tract [47]. In a questionnaire study of 59 patients with aspirin challenge-confirmed AERD, 83 percent reported respiratory reactions to a variety of alcoholic drinks, with symptoms usually developing within an hour of ingestion [61].
Chest pain — Patients with AERD may report a nonexertional angina-like chest pain. In a retrospective review of 153 individuals with AERD, 10 reported episodes of chest pain, which was associated in several cases with a peripheral blood eosinophilia [62]. The pain was retrosternal, heavy, or squeezing in nature and radiated into the jaw, neck, or arms, with accompanying diaphoresis, nausea, or lightheadedness. It did not improve acutely with nitrates or longer-term with antihypertensives or statins. Of the 10 patients, 8 had initiated high-dose aspirin therapy after undergoing an aspirin desensitization, and 6 of those patients reported that the chest pain began or worsened while they were on high-dose aspirin. Patients who underwent cardiac catheterization either had normal coronary arteries (without significant atherosclerosis) or showed evidence of coronary vasospasm. A course of glucocorticoids resulted in improvement or resolution in several patients. Until more is known about this entity, clinicians should be aware that patients with AERD may have angina-like chest pain in association with peripheral blood eosinophilia if no other cause can be identified. It has been speculated that the vasospasm may be related to eosinophils as indicated by the case report of resolution with steroid therapy, although further study is needed. The evaluation of coronary vasospasm is discussed separately. (See "Vasospastic angina".)
DIAGNOSIS — The diagnosis of aspirin-exacerbated respiratory disease (AERD) can often be made clinically when all three of the conditions that characterize AERD are present: asthma, visible nasal polyposis (or a history of nasal polypectomy), and a history of a typical reaction to a nonsteroidal anti-inflammatory drug (NSAID). A clinical diagnosis may be more difficult in patients with isolated asthma or isolated chronic rhinosinusitis (CRS) with nasal polyposis. In this case, a careful clinical history of symptoms following NSAID ingestion is required, possibly followed by diagnostic aspirin challenge, as discussed in the following sections.
The differentiation of pseudoallergic reactions, such as AERD, from allergic reactions to an individual NSAID is discussed in greater detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
Clinical diagnosis of NSAID reactions — When trying to determine whether a patient with asthma and/or nasal polyposis has had an adverse reaction to nonsteroidal anti-inflammatory drugs (NSAIDs), it is helpful to describe the symptoms of pseudoallergic reactions, as patients may not have previously recognized the association. NSAID sensitivity is an acquired condition, and the symptoms following NSAID ingestion are similar to flares in the underlying asthma and rhinosinusitis, so patients who were accustomed to taking these medications without difficulty often do not recognize the connection for some time. Clarifying the association with NSAID ingestion can be complicated, as the reason for NSAID ingestion, such as a respiratory infection or menstruation, may itself be a potential asthma trigger.
Some patients may not report NSAID-associated symptoms, as they have empirically avoided aspirin and NSAIDs for many years. Studies in which NSAID intolerance was diagnosed by challenge have reported higher rates among the general asthmatic population compared with those that rely on history alone [49]. Thus, the absence of a history of a reaction does not exclude NSAID sensitivity.
A small number of patients with NSAID intolerance may not recognize it because they are taking low daily doses of aspirin without obvious symptoms. This was observed in 7 patients in a series of 163 patients with AERD at one referral center [63]. Patients were taking 81 mg of aspirin daily. After stopping aspirin for at least 10 days, these patients had typical reactions to aspirin upon challenge, although with smaller decreases in forced expiratory volume in one second (FEV1) compared to other AERD patients. Four were subsequently desensitized to aspirin and responded to higher-dose therapy with improvements in nasal and asthma symptoms. Thus, the ability to tolerate low-dose aspirin therapy does not exclude the possibility of NSAID intolerance.
If the clinical history suggests a reaction to an NSAID, the clinician should then attempt to determine if the patient has reacted to more than one cyclooxygenase-1 (COX-1)-inhibiting NSAID, to exclude the possibility of an immunoglobulin E (IgE)-mediated reaction to a single NSAID. The patient should be questioned about any NSAID use SUBSEQUENT TO the first recognized reaction. NSAID ingestions BEFORE the first reaction are not relevant, since NSAID sensitivity is acquired, as reviewed previously. However, there is no evidence that previous NSAID use is required in order to develop NSAID sensitivity. Among patients with asthma and significant rhinosinusitis after a careful history, there is an 80 percent likelihood of having a positive oral aspirin challenge with a history of a single NSAID reaction [64]. This increases to 90 percent with a history of reactions to two different NSAIDs.
Cutaneous symptoms to NSAIDs usually signify a different type of NSAID reaction (eg, NSAID-induced urticaria/angioedema). However, occasional patients with AERD have blended reactions (mixed respiratory and cutaneous). Thus, the presence of urticaria/angioedema does not exclude the possibility of AERD. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Type 4: Blended reactions in otherwise asymptomatic individuals'.)
While the majority of NSAIDs are administered orally, reactions can occur with ketorolac given via intravenous or intramuscular injection or ophthalmic application.
Diagnostic aspirin challenge — Aspirin challenge is the only way to definitively diagnose type 1 pseudoallergy to NSAIDs, and thus AERD. Definitive diagnosis is important for research protocols involving AERD patients. Outside of research protocols, we typically reserve aspirin challenge for use as the first step in aspirin desensitization for patients with a specific need for regular NSAID therapy (ie, NSAIDs for rheumatologic disease, aspirin for cardiovascular disease, or aspirin for treatment of AERD).
●Types of challenge – Aspirin challenges are generally performed orally in the United States. In other areas (eg, Europe) a liquid lysyl-acetylsalicylic acid derivative is available for intranasal or bronchial challenge. Intranasal ketorolac is used in some research centers. However, inhaled challenges are purely diagnostic and not adequate for desensitization unless followed by oral aspirin. Protocols for aspirin challenge in patients with AERD are reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Challenge protocols and procedures'.)
●Premedication – In preparation for oral aspirin challenge or desensitization, patients with suspected AERD are usually pretreated with leukotriene-modifying agents (LTMAs), as these medications have been shown to dramatically reduce the severity of pulmonary reactions during the procedure. Despite the reduction in pulmonary symptoms, nasal and ocular symptoms still occur in most patients, such that the outcome of challenge should be apparent to the experienced clinician. Antihistamines are withheld for a week prior to the procedure, as they tend to blunt the nasal symptoms. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Premedication'.)
Nasal or inhaled glucocorticoids (eg, intranasal, inhaled, or in combination with a long-acting beta-agonist) that are part of the patient's usual regimen should be continued up to and during the procedure. These medications decrease the likelihood of a serious episode of bronchoconstriction, but enough of the manifestations are not suppressed to enable a diagnosis of aspirin sensitivity. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Provocation of symptoms'.)
●Staffing and location of challenge – Aspirin challenges are usually performed by allergy or pulmonary specialists with the expertise to manage any resultant symptoms and in settings equipped with the necessary medications, equipment, and support staff to manage acute bronchoconstriction or anaphylaxis.
●Challenge procedure ─ Oral aspirin challenge procedures vary among institutions, but generally start with a low dose of aspirin, such as 30 to 41.5 mg, and advance by doubling doses approximately every three hours. The details of aspirin challenge are provided separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Oral aspirin challenge and desensitization'.)
MANAGEMENT — The management of aspirin-exacerbated respiratory disease (AERD) involves guideline-based treatment of the patient's asthma and chronic rhinosinusitis (CRS), in addition to suppression of the consequences of abnormal leukotriene metabolism. Patients must avoid all cyclooxygenase-1 (COX-1)-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) or, in selected cases, undergo aspirin desensitization followed by daily NSAID therapy.
Asthma — National and international guidelines for asthma management apply to patients with AERD, except that leukotriene-modifying agents (LTMAs) are administered in most cases to improve both pulmonary and sinonasal symptoms. (See 'Leukotriene-modifying agents' below.)
Asthma management utilizing a step-wise approach is discussed elsewhere. (See "An overview of asthma management" and "Treatment of moderate persistent asthma in adolescents and adults" and "Treatment of severe asthma in adolescents and adults".)
Chronic rhinosinusitis with nasal polyposis — The medical and surgical management of CRS with nasal polyposis are presented separately. (See "Chronic rhinosinusitis: Management".)
Leukotriene-modifying agents — LTMAs should be part of the management of all patients with AERD to address the underlying dysregulation of leukotriene production and also protect patients from severe exacerbations due to accidental NSAID exposure. Both leukotriene-receptor antagonists (LTRAs) (eg, montelukast, zafirlukast) [38,39,65,66] and inhibitors of leukotriene synthesis (eg, zileuton) [37,67] are effective in AERD. The general use of LTMAs in asthma is reviewed separately (figure 3 and table 2). (See "Antileukotriene agents in the management of asthma".)
As a practical matter, most clinicians select an oral LTRA (montelukast, zafirlukast) for initial therapy, rather than the 5-lipoxygenase (5-LO) inhibitor zileuton, as zileuton requires twice daily administration, periodic monitoring of liver function tests, and has some potential drug interactions. If patients do not improve with the LTRA after four to six weeks, then zileuton may be added or substituted. In a survey of patients with AERD, respondents identified zileuton as "extremely effective" more often than LTRAs [47].
The following studies demonstrate that the addition of a LTMA to preexisting therapy improves respiratory tract symptoms in patients with AERD [14,65,67]:
●A randomized trial compared montelukast with placebo in 80 patients with asthma and NSAID intolerance, the majority of whom required inhaled or oral glucocorticoids to control their symptoms [65]. Four weeks of treatment with montelukast was associated with a 10 percent increase in forced expiratory volume in one second (FEV1), higher morning peak flow rates, decreased use of rescue medication, and a significant improvement in asthma quality of life scores. The montelukast group also experienced 54 percent fewer asthma exacerbations.
●A randomized trial evaluated the effect of six weeks of treatment with the 5-LO inhibitor zileuton (600 mg, four times daily) in 40 patients with AERD [67]. Existing therapy was continued, which included medium to high doses of inhaled (average daily dose >1000 micrograms of beclomethasone or budesonide) or oral glucocorticoids (4 to 25 mg daily) for all but one patient. The addition of zileuton compared with placebo resulted in both immediate and ongoing improvement in pulmonary function and lower use of short-acting beta-agonists for symptom relief. Zileuton also alleviated nasal symptoms, including rhinorrhea, congestion, and impaired sense of smell. Furthermore, zileuton produced a small reduction of bronchial hyperresponsiveness to histamine.
While the simultaneous use of zileuton and a LTRA has not been formally studied, it has been mentioned in case series and reviews [68-70]. It is thought that combination therapy may be advantageous in patients who do not achieve disease control with either of the individual agents. The rationale for combination therapy is based upon studies demonstrating that patients with AERD have elevated cysteinyl leukotriene (cysLT) levels and receptor numbers, as well as upregulation of 5-LO. Thus, combination therapy may address these abnormalities more completely.
NSAID avoidance — Patients with AERD should avoid all nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-1 (table 3), unless they have been desensitized to aspirin. Patients with AERD usually tolerate the following alternatives for the treatment of pain and/or inflammation, although exquisitely sensitive patients may react to higher doses of nonacetylated salicylates or acetaminophen:
●NSAIDs with very weak COX-1 inhibitory properties (eg, nonacetylated salicylates, such as salsalate and others)
●Acetaminophen (at doses up to 650 mg; as many as 20 percent of AERD patients will react to a dose of 1000 mg) [71]
●Highly selective COX-2 inhibitors (eg, celecoxib) [72]
The use of these alternative agents in patients with AERD is reviewed separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Types 1 to 4: Treatment options'.)
Aspirin desensitization — Nearly all AERD patients can be successfully desensitized to aspirin (acetylsalicylic acid, ASA). The mechanism through which ASA desensitization alters a patient's response to NSAIDs is not completely understood. One theory proposes that desensitization and subsequent daily aspirin treatment reduces interleukin-4 (IL-4)-induced expression of leukotrienes by inhibiting the transcription factor, signal transducer and activator of transcription 6 (STAT-6) [73,74].
The protocol for desensitization is essentially a continuation of the challenge procedure. (See 'Diagnostic aspirin challenge' above and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)
Indications — The indications for aspirin desensitization in AERD include the following:
●Nasal polyposis that is worsening or recurring after surgery despite LTMAs, nasal glucocorticoids, and other appropriate therapies
●Inflammatory conditions requiring daily NSAID therapy (eg, arthritis)
●Atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin
●Recurrent headaches or other conditions requiring intermittent use of NSAIDs after failure of other options
In each of these settings, an individualized approach is needed to determine the likelihood that the patient will benefit and adhere to the maintenance program of daily ASA/NSAIDs. The risk for gastrointestinal toxicity should be assessed and reviewed with the patient.
Patients with type 4 or blended reactions with a history of urticaria occurring as part of a respiratory reaction to NSAIDs (particularly more than one NSAID) are less likely to experience successful desensitization. A minority of patients will not be able to complete the aspirin desensitization procedure because of refractory nausea, abdominal pain, diarrhea, or the appearance of an erythematous, pruritic, macular dermatitis [12,18]. Rarely, a patient may develop lower respiratory symptoms that do not resolve between doses.
Efficacy of aspirin desensitization for AERD treatment — Daily aspirin therapy can reduce upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), although the effects on rhinosinusitis symptoms are typically more dramatic than the effects on asthma. Of note, there are no data to suggest aspirin is of benefit in the treatment of airway disease in patients with asthma and nasal polyposis, but without aspirin intolerance. The efficacy of daily aspirin therapy in treating upper and lower airway disease in patients with AERD and the dosing of aspirin in this setting are reviewed in greater detail elsewhere. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Efficacy of aspirin therapy in AERD'.)
Maintenance of desensitization — Patients who are successfully desensitized to ASA must continue to take aspirin or another COX-1-inhibiting NSAID daily in order to maintain the desensitized state. However, only aspirin (not other NSAIDs) has been shown to be useful in slowing the regrowth of nasal polyps and improving asthma symptoms over time.
●For patients with AERD and difficult-to-control asthma or nasal polyposis that is worsening or recurring despite LTMAs, nasal and inhaled glucocorticoids, and other appropriate therapies, aspirin desensitization is followed by daily aspirin (325 mg twice daily or 650 mg twice daily). Optimal dosing is reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Optimal aspirin dose for AERD'.)
●Aspirin desensitization followed by daily aspirin can be used in patients with atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin. Patients who take 81 mg of aspirin daily for cardioprotection will remain tolerant of this low dose of aspirin, although they will almost always NOT be able to tolerate larger doses of aspirin or be cross-desensitized to other NSAIDs. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Other issues of aspirin dosing after desensitization'.)
●Aspirin desensitization followed by a daily NSAID (other than aspirin) can be used by patients with inflammatory conditions requiring daily NSAID therapy. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Cross-desensitization to other NSAIDs'.)
●Patients who have undergone aspirin desensitization and wish to use other NSAIDs intermittently (eg, for musculoskeletal pain, headaches, or dysmenorrhea) should take at least 325 mg of aspirin daily to maintain the desensitized state. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Cross-desensitization to other NSAIDs'.)
●When aspirin therapy is interrupted, there is a "refractory period" of at least two to three days, but not more than five days, during which the patient can restart aspirin therapy without developing symptoms. The management of missed doses is discussed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Missed doses'.)
The development of gastric irritation from daily aspirin is reported by up to one-half of patients, although not all of these patients have symptoms severe enough to cause them to stop therapy. Tolerance of daily aspirin in patients with AERD is reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Reasons for discontinuation'.)
Biologic agents — Omalizumab and mepolizumab have both been studied in the treatment of patients with AERD.
Omalizumab — A small trial suggested that omalizumab (an anti-immunoglobulin E [IgE] monoclonal antibody) may be helpful in patients with nasal polyps [75]. In 24 patients with CRS with nasal polyposis and concomitant asthma, approximately one-half of whom had AERD, subjects received four to eight subcutaneous doses of omalizumab (n = 16) or placebo (n = 8), consistent with omalizumab dosing guidelines for asthma (based on serum IgE level and body mass) [75]. Omalizumab treatment was associated with improved airway symptoms and quality of life, and with a significant decrease in total endoscopic nasal polyposis scores after 16 weeks compared with placebo. Changes in polyposis scores were confirmed by means of sinus computed tomography (CT) scoring (Lund-Mackay score) and were independent of the presence of allergy. However, in the subset of patients with AERD, improvement was not clearly observed on CT. Thus, it is unclear whether this effect is specific to AERD.
In two case reports of patients with AERD and severe asthma, omalizumab was associated with clinical improvement in asthma and loss of ASA sensitivity to oral aspirin challenge [76,77]. In a separate report, omalizumab was associated with improved asthma control and loss of sensitivity to nasal lysine-aspirin challenge [78].
Omalizumab is approved by the US Food and Drug Administration (FDA) for the treatment of inadequately-controlled moderate-to-severe asthma and could be considered for patients with concomitant CRS with nasal polyposis. We have used omalizumab in a small number of patients with severe AERD who cannot take aspirin or have not improved sufficiently with aspirin therapy, with mixed results. (See "Anti-IgE therapy".)
Mepolizumab — Mepolizumab is an anti-IL-5 monoclonal antibody that was studied in patients with severe asthma and blood or sputum eosinophilia, as reviewed elsewhere. (See "Investigational agents for asthma", section on 'Anti-IL-5 monoclonal antibodies'.)
In a small randomized trial of patients with severe nasal polyposis refractory to glucocorticoid therapy, subjects received two doses of intravenous mepolizumab 28 days apart, or placebo, and the primary outcome was total polyp score as evaluated by nasal endoscopy at two months [79]. Five of 20 patients in the mepolizumab arm were aspirin intolerant and 10 had asthma. After two months of treatment, 12 of 20 patients in the mepolizumab arm had a significant reduction in total polyp score, compared with one in the placebo arm. Although this study had significant limitations, such as a high overall dropout rate and an unclear number of patients with confirmed AERD, the results suggest that eosinophil-specific therapies may be of some benefit for the eosinophilic nasal polyposis that is common in AERD. However, whether mepolizumab provides specific additional benefit in AERD, beyond what would be predicted from the eosinophilic nature of the asthma and nasal polyps of AERD, is still unclear.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic rhinosinusitis".)
●Aspirin-exacerbated respiratory disease (AERD) (also called NSAID-exacerbated respiratory disease or NERD) describes patients with asthma and chronic rhinosinusitis (CRS) with nasal polyposis, who experience acute upper and lower respiratory tract symptoms following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). AERD affects 5 to 20 percent of all patients with asthma. Reactions to NSAIDs typically begin 30 minutes to 3 hours after ingestion and present as a sudden worsening of asthma and nasal congestion, sometimes accompanied by other symptoms. (See 'Clinical presentation' above.)
●The pathophysiology of AERD involves acquired perturbations in arachidonic acid (AA) metabolism and a resulting imbalance between proinflammatory and anti-inflammatory mediators, leading to chronic airway inflammation. The pharmacologic action of cyclooxygenase-1 (COX-1)-inhibiting NSAIDs acutely exacerbates this imbalance, and also results in mast cell activation. (See 'Pathophysiology' above.)
●A working diagnosis of AERD is usually made clinically based upon the presence of the characteristic component disorders (ie, asthma, CRS with nasal polyposis, and a history of NSAID reactions). Definitive diagnosis requires aspirin challenge, although this degree of diagnostic precision is rarely needed outside of research protocols. (See 'Diagnosis' above and "Diagnostic challenge and desensitization protocols for NSAID reactions".)
●Patients with AERD require guideline-based therapy for asthma and medical and surgical management of CRS with nasal polyposis. (See "An overview of asthma management" and "Chronic rhinosinusitis: Management".)
●For patients with AERD and moderate-to-severe asthma, we recommend adding a leukotriene-modifying agent (LTMA) to their other asthma therapy (Grade 1B). We usually begin with a leukotriene-receptor antagonist (LTRA) (eg, montelukast, zafirlukast). If there is no clinical improvement after four to six weeks, we add or substitute the 5-lipoxygenase (5-LO) inhibitor zileuton. (See 'Leukotriene-modifying agents' above.)
●For patients with AERD and nasal symptoms despite other therapies, we recommend a LTMA even in the absence of asthma (Grade 1B). (See 'Leukotriene-modifying agents' above.)
●Patients with AERD should avoid all NSAIDs that inhibit COX-1 (table 3), unless they have been desensitized to aspirin. (See 'NSAID avoidance' above.)
●Aspirin desensitization followed by daily aspirin (or sometimes daily NSAID) therapy may be beneficial in carefully selected patients with AERD and one of the following disorders (see 'Aspirin desensitization' above):
•Nasal polyposis that is worsening or recurring despite intranasal glucocorticoids, surgery, and other appropriate therapies.
•Inflammatory conditions requiring daily NSAID therapy that cannot be treated with selective COX-2 inhibitors.
•Atherosclerotic heart/vascular disease requiring the antiplatelet effects of aspirin.
•Recurrent headaches or other conditions requiring intermittent use of NSAIDs.
●Aspirin desensitization is usually performed by allergists or pulmonologists with expertise in the technique and in a setting that is equipped to treat the range of reactions that may result. Following desensitization, patients must ingest aspirin or an NSAID daily to maintain the desensitized state. The choice and dose of aspirin or NSAID for ongoing therapy depends on the indication for desensitization. As long as the desensitized state is maintained, the patients can tolerate different COX-1-inhibiting NSAIDs interchangeably. (See 'Aspirin desensitization' above and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)
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- Kowalski ML, Pawliczak R, Wozniak J, et al. Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients. Am J Respir Crit Care Med 2000; 161:391.
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- Laidlaw TM, Cutler AJ, Kidder MS, et al. Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2014; 133:1692.
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- Emanuel IA, Shah SB. Chronic rhinosinusitis: allergy and sinus computed tomography relationships. Otolaryngol Head Neck Surg 2000; 123:687.
- Poznanovic SA, Kingdom TT. Total IgE levels and peripheral eosinophilia: correlation with mucosal disease based on computed tomographic imaging of the paranasal sinus. Arch Otolaryngol Head Neck Surg 2007; 133:701.
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- Cardet JC, White AA, Barrett NA, et al. Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol Pract 2014; 2:208.
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- Dahlén SE, Malmström K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:9.
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text: On 2/20/12 11:55 AM, deadalnix wrote: > Le 20/02/2012 18:11, Andrei Alexandrescu a écrit : >> On 2/20/12 11:05 AM, foobar wrote: >>> On Monday, 20 February 2012 at 16:37:28 UTC, Andrei Alexandrescu wrote: >>>> On 2/20/12 10:16 AM, Nick Sabalausky wrote: >>>>> "Andrei Alexandrescu"<SeeWebsiteForEmail at erdani.org> wrote in message >>>>> news:jhtq31$u8q$1 at digitalmars.com... >>>>>> >>>>>> Again, I think this thread clarified we need the "Variant[string] >>>>>> info;" >>>>>> member however we define the hierarchy. >>>>>> >>>>> >>>>> I disagree. I don't see a need for that. >>>> >>>> How would we address custom formatting of e.g. error messages? >>>> >>>> Andrei >>> >>> Separation of concerns - exceptions are meant to notify the *developer* >>> of errors. User facing error messages is a separate concern that >>> exceptions should not be responsible for. it's not just outsourcing the >>> translation strings, it's the developer's job to determine what if at >>> all should be done with the exception. >> >> At the end of the day, a human-readable error message must be properly >> formatted given some exception that signaled an error. So I disagree >> that exceptions are meant for the developer. They are mechanism, a means >> to an end. >> >>> Trivial example: My mom enters a misspelled URL (e.g. goggle.com) in her >>> browser, she does not know or care what 404 means. instead she gets a >>> formated page suggesting her to check her spelling and probably a >>> suggestion to try google.com instead. >> >> Sure, and the question is how the message gets created. >> >>> the exception notifies the developer of the error, the developer does >>> extra processing (e.g. to suggest similar valid websites) and the user >>> get a friendly notification. clearly it doesn't make sense to put all >>> this into the exception. >> >> That extra processing must format the message given the information >> passed by the exception. _Definitely_ it doesn't make sense to put the >> formatting processing in the exception. That's why shipping the >> information outside the exception in a generic format is necessary, >> hence the Variant[string]. >> >> >> Andrei > > And so variant is the way to go ? > > Clearly, this is a very strong arguement in favor of typed Exception, > that provide usefull information about what went wrong. This is a safe > approach. This does not pit typed exceptions against uniform interfaces. The hash simply provides information in a uniform format across exception types. That way, code that needs to extract and format information in a generic manner can be written in one place. > Because this Variant stuff is going to require massive ducktyping of > Exceptions, with all possible errors involved. The keys in the > Variant[string] will depend on the Exception the dev is facing. This > should be avoided and should warn us about the requirement of typed > Exceptions. I agree. Again, this is not one against the other. Andrei

subset: commoncrawl


text:
Job Description: Part Time Executive Director Responsible for overseeing the administration, programs and, mission of the Arts Council of Rockland.
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David Curtis
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FOCUS Brands Inc.
David Curtis is the Senior Director of Retail Technology for FOCUS Brands. FOCUS Brands Inc. is the franchisor and operator of over 3,300 ice cream stores, bakeries, restaurants, and cafes in the United States and 50 foreign countries under the brand names of Carvel®, Cinnabon®, Schlotzsky's®, Moe's Southwest Grill®, Auntie Anne's® Pretzels, and the franchisor of Seattle's Best Coffee® on certain military bases and in certain international markets. Based in Atlanta, the primary objective of FOCUS Brands is to "FOCUS on making people happy."
David is responsible for the selection, development, and implementation of retail technology in support of each brand's retail operations and back office support and reporting systems. David has been with Focus Brands for 2 years and has worked on major initiatives with regards to back-of-house automation, PCI compliance, IT Governance, Digital Menu Boards, and the convergence of online, social, and mobile technology in support of operations, marketing, loyalty, and payment.
Prior to Focus Brands, David worked as the IT Director of Ted's Montana Grill, and has had extensive retail technology experience working for Urban Brands a specialty retailer of women's apparel. In addition, over his 25 year IT management career, David has had diverse IT experience working for companies such as Citicorp (now Citigroup) and Lifetime Television for Women.


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Craig, did you have to do any cool down laps in the 12C's? I did a track day in 100 F heat and the 12c's could only go 4 laps then needed a cool down at 45mph before doing 3 more laps then into pits to cool down. It was because the turbo's created incredible heat. Before any says well it's a super car, non turbo Ferraris (458, 430 & Scuderia's) pounded around the track with more consecutive and overall laps not needing anywhere near the same type of break to cool down. I was really surprised by that considering how great a company McLaren is. The 12c is a great car and seriously fast, but you feel kind of removed from the car compared to others that you feel a part of.
Lucky guy.... Getting to drive a McLaren around an F1 track for free is an opportunity not to pass up.


text:
Ok so it aberrantly works but it does eats all the packages so when ports
scan is done the scanner doesn't know if packet was delivered or not (not
good for testing, but also not good for hackers) PS: It = firewall
Another thing that is driving me crazy is that I can't loop through the wan
address within the local net.
Router Wan Address 188.8.131.52
PC connected to that router: 192.168.1.50 (Comp A)
HTTP Server on w/ that router: 192.168.1.51 (Server)
Now when I connect to 192.168.1.51:80 locally all is good, but when I use
Comp A and type WAN address http://22.214.171.124:80 im getting nowhere. I
think whats what the warning on the nat page setup said that it is
impossible to do!, but my D-Link router was able to do it and I damn need
that functionality! Does any one knows how to make it possible to work?
-----Original Message-----
From: Sven Brill [mailto:madde at gmx dot net]
Sent: Friday, September 29, 2006 9:48 PM
To: Alex M
Subject: Re: [m0n0wall] why cant i foward PORTS to my radius server?
Alex M wrote:
> Here is the setup:
> I set DMZ rule to pass anything from WAN to my local IP
> I created Inbound NAT Rule to forward 1812 and 1813 to my IP but when I do
> port scan it seams that all ports a stelthed. I even tried to rebut. but
> nothing happens :-(
couple of questions to isolate the problem:
what port scanner are you using?
are you scanning the the WAN interface from the outside?
which radius server is it?
are you sure it only listens on these ports, not maybe 2083 ("Secure
Radius") or any arbitrary port? 1812 and 1813 are the standard ports,
but can be configured differently.
can you see anything blocked in the logs (turn on "Log packets blocked
by the default rule" under Logs/Settings)?


text:
Business strategies in the U.S. communications and entertainment have recently been shaped profoundly by spectrum issues.
Dish Network once hoped to turn Blockbuster and some new re-purposed satellite spectrum into a mobile video service. The plan, in April 2011, was to retain some of the Blockbuster retail locations to sell mobile devices supporting the new proposed service.
Those plans floundered when the Federal Communications Commission didn't quickly approve a waiver allowing Dish to use its satellite spectrum for terrestrial data and voice transmission.
Image via Shutterstock
LightSquared has been unable to launch its proposed wholesale Long Term Evolution network, and might declare bankruptcy, because it has not been able to convince regulators of the merits of its plan to re-purpose satellite spectrum for use as an LTE network.
And though it is not the sole reason, desire to acquire spectrum assets is driving merger and acquisition efforts in the U.S. mobile business.
Even the fixed network business now is starting to be shaped by wireless access, as most fixed broadband connections now terminate using Wi-Fi, and support devices capable of using Wi-Fi networks. And the amount of such usage is important.
About 68 percent of consumer mobile phone use, for example, now occurs in the home, a study sponsored by AOL and BBDO has found. That, as much as anything, shows the growing importance of "untethered" access for mobile devices.
The study, conducted by research firm InsightsNow, shows that a focus on "mobile" devices actually requires understanding the role of untethered access, which in fact might already represent as much as half of all mobile operations on a smartphone.
"Me Time," activities that involve "seeking relaxation and entertainment in order to indulge oneself or pass the time" accounted for about 46 percent of all smartphone app and website activities, averaging 864 minutes per month per user. About 70 percent of those activities are "lean-back" experiences.
The need for more spectrum is driving strategy elsewhere as well.
AT&T wanted to buy T-Mobile USA in large part for its spectrum assets. Sprint's board considered, then rejected, an early 2012 bid to buy MetroPCS.
T-Mobile USA now wants to buy MetroPCS in part for its spectrum assets.
Verizon has gotten approval to buy mobile frequencies from Comcast, Time Warner Cable, Cox Communications and Bright House Networks.
AT&T is waiting for clearance of its purchase of more spectrum from NextWave.
The FCC now is trying to entice U.S. broadcasters to part with abandoned TV broadcast spectrum so it can be auctioned off to support U.S. Long Term Evolution networks.
And a rollout of "white spaces" spectrum might start in 2013 as commercial radios become available as well.
Contributing Editor
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text:
TinyButStrong is a template class for PHP that allows you to generate XML/HTML pages and any other files based on text source. The engine gives facilities to work with any databases, including in native PDO, MySQL, PostgreSQL, SQLite, PHP arrays, and more. It is possible to design templates using any visual editor (like Dreamweaver or FrontPage), and thus to make templates that are compatible with W3C standards for example. It features simple block management, useful display formats, conditional displaying for blocks and locators, remote XML/HTML attribute modification, a cache system, and the ability to include sub-templates and execute associated scripts. Plug-ins are supported since version 3.0.
TbsSQL is a small wrapper class for working with SQL databases within PHP scripts. It has few methods and two properties and it's only one file per database for installation. Its most interesting feature is that it can protect and format values before merging them into the SQL statement. It has a cache feature, a trace mode, a debug console, and it can return data as arrays, standard objects, specific class objects, or clone objects. It can also delete PHP connection variables after making the connection.
OpenTBS is a PHP tool that helps you to make OpenOffice and MS Office documents using templates. You first design your template using OpenOffice or MS Office, and then OpenTBS merges it with data that you supply from PHP code and databases. It has facilities to manage pictures. The resulting documents are saved to file, served for download, or returned as a string. In fact, OpenTBS can merge any OpenDocument files, any OpenXML files, and any XML files compressed in a Zip archive. No extra exe file is required and it makes no temporary files, since all work is done in memory. OpenTBS is based on the TinyButStrong template engine.
TbsZip is a PHP class that enables you to read and write Zip archives. The class doesn't require PHP extensions or temporary files. TbsZip can read, add, delete, and modify files stored in an archive. It can even start with an empty archive. The original archive is not modified. The new archive can be saved in the server as a new file, or provided directly as an HTTP download, or even as a binary string. If the Zlib extension is activated in PHP, then TbsZip can automatically compress and uncompress files in the archive.
A tool for securing DNS communications between a client and a DNS resolver.
A polyhedral extraction tool (PET).


text:
Charity Entertainment Night at Bella Vista Brazilian Pizza
Reading, Writing, It's Exciting!
Monday, April 29, 2013 from 6:30 PM to 9:00 PM (PDT)
Who's Going
San Francisco, California
London, United Kingdom
Florence, Italy
Event Details
"Reading, Writing, It's Exciting" is staging charity entertainment singing nights at Bella Vista Brazilian Gourmet Pizza.
Bella Vista will donate 20% of any food bought during the event to the RWE Literacy charity... There is no ticket charge for attendees.
We are excited to announce the lineup for this 4/29 show (this time featuring all young performers from ages 12-17):
- Franchesca Maia
- Zoe Concha
- J'Rose
- Lauren Taylor
- Conner Taylor
So come on out and enjoy some great music by a group of talented youngsters!
When & Where
Bella Vista Brazilian Gourmet Pizza
10826 Venice Blvd
Culver City,
Monday, April 29, 2013 from 6:30 PM to 9:00 PM (PDT)
Add to my calendar
Reading, Writing, It's Exciting!
RWE is a nonprofit literacy program that mentors kids who need the most help with writing and reading.
For information, please go to: http://rweprogram.org/site/


text:
The impact of climate change will go beyond an increase in extreme weather events to threaten U.S. economic and national security interests, a new Harvard study concludes. "Lessons from the past are no longer of great value as a guide to the future," says Michael McElroy, Gilbert Butler Professor of Environmental Studies at Harvard University and co-lead author of the study. "Unexpected changes in regional weather are likely to define the new climate normal, and we are not prepared." "We are not prepared." So what exactly are we not prepared for?
The important societal implication of global warming in the near term is not that portions of the earth are going to experience higher temperatures, increased precipitation and
increased droughts; it is that the extremes are likely to become more prevalent and more
frequent. What was once a 1 in 100 year anomaly is likely to become a 1 in 10 or 1 in 30
year anomaly or even more frequent in the near future. Our infrastructure and agriculture
is not designed to accommodate the increasing frequency and prevalence of such
extremes. Human security and the interests of most nations are at stake as a result of such
increasing climate stress. The national security context will change. The potential for
profound impacts upon water, food and energy security, critical infrastructure, and
ecosystem resources will influence the individual and collective responses of nations
coping with climate changes. U.S. national security interests have always been influenced
by extreme weather patterns. Now the risks will become larger and more apparent. The
study renders the judgment that the increasingly disruptive influences of climate extremes
necessitate their careful consideration in threat analysis, mitigation, and response. It is
in the best interest of the U.S. to be vigilant about extreme weather patterns, the behavior
of nations in their attempts to mitigate or adapt to the effects of changing extremes, andimpacts on social, economic, and political well-being.
Or we can just stop making God angry! Thanks global warming deniers, their media enablers and the stooge politicians who do the bidding of energy companies for making sure we're not prepared for the droughts, floods, severe storms, heat waves and wars over water and food that appear destined to be a staple of our children's futures. Good job. Now read this:
10 things that happen to our bodies during space flight
Spidernaut never got to enjoy its fame
Polar ice sheets continue to melt, but climate-change deniers remain thick as ever


text:
RSS Feeds From TESSCO.com
About RSS Feeds
Really Simple Syndication (RSS) is an easy and free way to get vital information on the latest products from TESSCO - as soon as they appear - even if you are not logged onto TESSCO.com. Want up-to-date news of product introductions and the latest online TESSCO Knowledge Tools? You choose what you want to track and how often you want to be updated.
Using RSS
To read RSS feeds you'll need to use either a compatible Web browser or a news reader - a program that provides a real-time interface to the feeds you select. TESSCO has adopted Internet Explorer 7 for the initial introduction of RSS Feeds, but the TESSCO.com RSS feeds will work with any reader using the standard XML-based format.
Click this link for step-by-step help - Internet Explorer RSS Feed Setup Tutorial
Why Subscribe?
By subscribing to a feed, your browser or feed reader will automatically update your view of the updated information. You will have controls for sort order (newest or oldest first) and the maximum number of entries you want to keep.
See Everything
RSS feeds present only the most recent product introductions. To see TESSCO's complete offering of wireless products, solutions, and services, visit TESSCO.com.
Product Category
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Please send your comments and suggestions to email@example.com


text:
UP TO 50% OFF > MENS SALE & WOMENS SALE | Free Shipping on orders over 40€
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text:
Welcome to 44holidays.com - The UK's Brightest Holiday Comparison Website!
44holidays is a holiday comparison website with live travel comparison searches that makes finding your next holiday easy. Whether you're looking for an all-inclusive holiday or if you're searching for last minute holiday deals and holiday bargains, 44holidays is the only holiday comparison you need!
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With millions of holiday offers available at any time, including package holidays, skiing holidays, cruises and city breaks, 44holidays is one of the largest travel comparison websites in the UK.
From weekends away to city breaks to holidays abroad, 44holidays is your complete travel partner.
44holidays - Where holidays are made!


text:
Touching the Masses
We have evolved as a society leaps and bounds over the last couple of decades. We are the constant beneficiaries of new technologies, intellectual advances, and revolutionary ideas. As an inspiring college student, I look to put myself in the most advantageous position for future success and nothing makes me happier than the potential of creating and/or marketing a product to the general public that will bring a smile to every face every that uses it. As a marketing major, I have grand visions for my future, and I believe whole heartedly that I will create and/or play a major role in introducing the modern society to the next million dollar idea. From my youth, I'm proud to say that I've always possessed an entrepreneurial type mind set. I am determined to take the world by storm by making a lasting imprint that will last a life time. I look up to businessmen/entrepreneurs such as Mark Zuckerburg, co-founder of Facebook, Evan Spiegel, co-founder of Snapchat, and Kevin Systrom, co-founder of Instagram as blueprints for success for myself. All three of the above mentioned moguls created products that can touch millions of lives at a time. These type of guys can be credited with playing a major role in the progression of modern ideas and it excites me to potentially be a part of the next movement. I'm young and motivated to make peers and strangers alike unified as I work to progress us even farther into the future!


text:
Easton was named as a trialist for Saturday's Second Division meeting with Cowdenbeath but signed for Brian Reid's outfit after the game.
However, Easton was unable to prevent a 2-0 defeat for his new side.
The defender had left Tannadice "by mutual consent", according to United's website, after making just one first-team start for the SPL club.
Easton, who also made seven substitute appearances, had spent the first half of the season on loan with Stirling Albion in Division One.
What are these?


text:
Freshman shoots a third round 69; Lions finish fifth
VALDOSTA, Ga. – Saint Leo University men's golfer Ryan Gendron shot a third round score of 69, and three-round total of 210, to take medalist honors at the First Federal Southeastern Collegiate held at Kinderlou Forest Golf Club in Valdosta, Ga. As a team, the Lions finished fifth with a three-round score of 881 (296-294-291) just two strokes behind host Valdosta State (879).
Before his 69 in the third round on Tuesday, Gendron, a freshman from Tampa, finished the first day tied for second place after shooting under par (71-70) in the first two rounds on the par-72 course.
Shooting a one-over par 73 in the third round were sophomore Liam Ainsworth (74-74-73) and freshman Joey Savoie (77-74-73), earning the duo a share of 23rd and 35th, respectively.
Sophomore Trevor Joseph finished tied for 65th with a three-day total of 232 (74-76-82), while freshman Casey Bannon was tied for 69th with a 233 (78-79-76) over the two days.
Barry University, the No. 1 ranked team in the nation, won the two-day 18-team event shooting an 861 for three rounds, six strokes ahead of second place – and No. 2 ranked – Lynn University (867). Armstrong State (878), ranked No. 9 in the nation, rounded out the top three teams.
Next up for Saint Leo, the Lions will take part in the Panther Invitational hosted by Florida Tech at Majors Gold Club in Melbourne, Fla., March 17-18.
For more on the Saint Leo University men's golf team visit SaintLeoLions.com. Also be sure 'Like' the Lions on Facebook and 'Follow' the Lions on Twitter and Instagram.


text:
Jonah Hill Addresses His Controversial Remarks
Jonah Hill is an actor, writer and producer best known for starring in the films Knocked Up, Superbad, Forgetting Sarah Marshall and This Is the End. He scored Oscar nominations for his work in Moneyball and The Wolf of Wall Street. Hill also wrote and starred in 21 Jump Street and its sequel, 22 Jump Street. He next voices Carl in Sausage Party and stars in War Dogs.


text:
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A Guide To College Resource And Financial ManagementTaylor and Francis 2013; US$ 50.95
This text is part of the "Managing Colleges Effectively" series that is designed for managers at all levels and governors of colleges in the new further education sector who are undertaking new and enhanced management tasks and responsibilities arising out of incorporation. This book is also relevant to similar areas in schools - particularly grant... more...
Polyamine Drug DiscoveryRoyal Society of Chemistry 2011; US$ 213.00
This is the first comprehensive description of the discovery and therapeutic potential of polyamine drugs. more...
Divine Promise and Human Freedom in Contemporary Catholic ThoughtLexington Books 2015; US$ 99.00
A series of studies in metaphysics, historical theology, moral theology, and political philosophy, Divine Promise and Human Freedom in Contemporary Catholic Thought offers the insights of separate analyses employing distinctive methods proper to individual disciplines, through which there nonetheless runs the common Catholic focus on the sacramental,... more...
World-Systems Theory in PracticeRowman & Littlefield Publishers 1998; US$ 58.00
In the quarter century since Wallerstein first developed world systems theory (WST), scholars in a variety of disciplines have adopted the approach to explain intersocietal interaction on a grand scale. These essays bring to light archaeological data and analysis to show that many historic and prehistoric states lacked the mechanisms to dominate the... more...
Handbook of Public SociologyRowman & Littlefield Publishers 2009; US$ 52.00
The Handbook of Public Sociology presents a comprehensive look at every facet of public sociology in theory and practice. It pays particular attention to how public sociology can complement more traditional types of sociological practice to advance both the analytical power of the discipline and its ability to benefit society. The volume features... more...
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text: By Pete Najarian, co-founder of OptionMonsterNEW YORK -- United Parcel Service has pulled back from this year's highs but some bulls are hoping that it will deliver some profits. OptionMonster's tracking systems detected a large institutional trade in the transportation and logistics company Monday. A trading sold about 13,000 April 80 calls for $1.76 and rolled the position to the July 85 calls, which were bought for 86 cents. Calls lock in the purchase price for the stock, so they can generate some nice leverage in the event of a rally. But these options will lose value if the shares don't rise within the designated time frame, so Monday's trader adjusted his or her position to pick up another three months of upside exposure while looking for the stock to rise an additional $5. UPS was down fractionally Monday to close at $79.91. It sold off hard in late December after failing to break above its 200-day moving but then ripped to a new January high before easing back from that level in recent days. Overall calls in the name outnumbered puts by about 29,200 to 3,300 Monday, a reflection of the session's bullish sentiment. Its total option volume was twice the average amount. Najarian owns UPS calls.


text:
Recording overheads isn't all high frequencies: a great cymbal or overhead mic hears the sparkle and wash of the crash and ride, but it also hears the full mids and deep lows produced by the rest of the kit - crucial to a huge-sounding drum mix.
"The sound achieved was clear and accurate with transients handled well and a high-end presence...while the sound was quite loud, the pair are able to take high SPLs and handled it with no problem."
- Trevor Curwen, Future Music / Music Radar (full review)
Voodoo VR1
"These ribbons are magic on overheads."
- Jack Douglas, Producer/Engineer (Aerosmith, John Lennon)
The RN17
"The RN17 has become my desert island microphone. If there was one microphone I knew I could take with me that would get me out of trouble, it's this...The clarity and the detail I get is wonderful, especially for one of the things I do a lot of, which is sampling - this is a perfect sampling microphone, because it has that reality that you need, with low noise, but it also has just a little bit of extra something."
- Simon Franglen, GRAMMY®-winning Composer / Producer / Musician ('Avatar', 'Titanic', 'Skyfall') - sE Artist


text:
SMEs Missing Out on Benefits of the Digital Eco
Press Release – MYOB
SMEs using internet technology more likely to see rise in revenue Only 16% of NZ businesses using cloud computing
24 June 2013
Too Many NZ SMEs Missing Out on Benefits of the Digital Economy
• SMEs using internet technology more likely to see rise in revenue
• Only 16% of NZ businesses using cloud computing
Local businesses are unknowingly missing out on the breadth of opportunities offered by the digital economy, according to new research into New Zealand SME's online technology usage. With the findings also clearly highlighting the breadth of opportunities it offers, MYOB is calling for vastly improved government education and support for the business community.
According to the latest MYOB Business Monitor, a survey of 1,000+ SMEs with anywhere between 0-200 employees, only 16% of New Zealand businesses used cloud computing and only 34% of SMEs operated a business website.
MYOB New Zealand general manager – business division, James Scollay, says there is tremendous scope for SMEs to increase revenue, strengthen customer relationships and improve productivity through using online technologies.
"There is an immense need in this country for government and business leaders to work together with our business community to share knowledge about the benefits of embracing online tools. And it must happen now. Even the simplest tips can make the world of difference to a business and every business is important – they provide the livelihood for hundreds of thousands of local families and contribute greatly to the domestic economy," he says.
"Our research found that business owners using cloud technology say it enhances their data security and improves their productivity, while those with a website earn more, sell more and have better relationships with their clients. Activities such as building an online presence, enabling teleworkers, using online accounting software, building a social media presence and so on really should be easy to implement for businesses of all shapes and sizes.
"The majority of local businesses are missing out on these benefits. Clearly we need to think about how to better support business operators in taking up these technologies."
Tech-savvy businesses doing better
According to the MYOB Business Monitor, which was commissioned to Colmar Brunton, businesses using internet technology are much more likely to report a rise in annual revenue than non-users. They are also more optimistic about their own performance and that of the wider economy.
"SMEs that have a business website are almost 10% more likely to have reported a revenue increase in the last year than those without, while those that have embraced cloud computing are 16% more likely to have seen a rise. Both groups are anticipating further revenue increases throughout 2013. This is the sort of knowledge that local business operators will benefit from when working on their growth plans," says Mr Scollay.
"Interestingly, businesses using the cloud are also more likely to be investing in growth strategies and expanding their range of products and services. At MYOB, we've experienced firsthand the benefits of cloud technology and around one third of our new product registrations are for cloud based solutions.
"I believe this technology offers SMEs a transformative advantage – making it easier to work whenever and wherever they want, as well as share and collaborate more effectively."
The power of the cloud
Internet usage among consumers is well established, with 86% of New Zealanders using the internet daily and 80% searching online before buying a product or service .
"This really highlights the stark difference between businesses' adoption of the internet and the demands of their customers," says Mr Scollay.
"Although online technology is ubiquitous in the workplace, the Business Monitor research suggests SMEs are still uncertain about the cloud. More work needs to be done in ensuring owners and managers understand the specific gains to be had from embracing cloud innovation and exactly how the technology will help produce improved business results."
According to the MYOB Business Monitor, the top five reasons why SMEs use cloud computing are:
1. Ability to work from whatever locations they want, or need, to work from (68%)
2. Data is better protected and safer online rather than on their own server (49%)
3. Enables one or more staff members to work remotely (42%)
4. Enables accounting software to receive direct feeds of bank transactions (36%)
5. Enables employees and the business owner/manager to be more productive (29%)
"The cloud provides a highly secure means of storing and sharing data, and supports improved productivity. It also allows business teams the freedom to work from locations other than the office. Given that our research has found businesses with remote workers are more productive and profitable, this is a significant benefit," says Mr Scollay.
The Business Monitor found SMEs with remote workers were 43% more likely to see a revenue rise in the past year.
Why SMEs resist cloud technology
Despite the growing range of cloud computing options available for business, New Zealand SMEs remained unsure of the technology. 84% of the country's businesses were either still not using it or unsure if they were using it.
SMEs said the top three reasons for not implementing cloud computing were:
1. Not knowing enough to make the right business decisions about it (33%)
2. Not tech-savvy enough and don't feel confident about starting to look at it for their business (22%)
3. Unsure of data safety when using overseas servers (19%)
"It is clear that business owners and managers do not feel confident enough to take up the technology, with over half needing more support or information to make the change," Mr Scollay says.
"Understandably, the issue of security is top of mind for many local business operators. In reality, the systems and processes available from leading cloud providers are likely to be significantly more secure than SMEs' own systems. However, a number of providers use 'quick and dirty' methods of sharing data – like the practice of 'screen-scraping' for bank feeds. This could put the credibility of the technology at risk."
Use of the cloud around the country
Of the three main centres, Auckland SMEs were most likely to use the cloud (19%). However, a higher proportion of businesses in the Manawatu-Wanganui and Bay of Plenty region were using the cloud than in Auckland. 21% of the Manawatu-Wanganui businesses and 20% of Bay of Plenty businesses were doing so.
Results were not as promising in Otago and Southland, Hawkes Bay, and Waikato, with the regions posting the lowest results for cloud usage.
Region % of SMEs using the cloud Region % of SMEs with a website
Main centres Main centres
Auckland 19% Auckland 43%
Christchurch 17% Christchurch 34%
Wellington 12% Wellington 33%
Regions Regions
Manawatu-Wanganui 21% Hawkes Bay 36%
Bay of Plenty 20% Manawatu-Wanganui 28%
Northland 19% Bay of Plenty 32%
Otago & Southland 16% Waikato 26%
Hawkes Bay 11% Northland 25%
Waikato 10% Otago & Southland 20%
Business types benefiting from internet technology
The finance and insurance sector (29%) had the largest number of SMEs that have embraced the cloud, while the transport, postal and warehousing industry (7%) had the fewest. The primary (10%) and construction and trades (10%) sectors also reported low usage of cloud technology.
"Businesses owned by the oldest generation, Traditionalists, have the lowest uptake of both the cloud and business websites, while those owned by Generation X were the most technology savvy," says Mr Scollay. "Interestingly, Generation Y are described as 'digital natives', and you would expect that they would be ahead of their older peers when it comes to use of the cloud and ownership of a business website. In reality they are behind Gen X in cloud usage and on par with their peers for using business websites."
Age of owner % of SMEs using the cloud Age of owner % of SMEs with a website
Generation X 19% Generation X 36%
Baby boomers 16% Baby boomers 36%
Generation Y 16% Generation Y 35%
Traditionalists 11% Traditionalists 16%
"Cloud computing supports improved productivity and security, while opening up a range of accessible tools for better business management and geographical freedom. Having a website increases your chances of attracting new clients, giving access to both the local and international market. Most importantly, it gives businesses a dynamic presence online – where most of their customers are shopping," says Mr Scollay.
"As part of a small economy that's geographically distant from the rest of the world, it's vitally important that local businesses look to gain every possible advantage. Few opportunities are as potentially transformational as the internet. It's clear there is still considerable scope for developers, business advisors and the government to invest more time and energy in ensuring New Zealand business operators understand all the potential benefits of this technology."
Content Sourced from scoop.co.nz
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