Effect of ambient air pollution on the incidence of appendicitis

Background

The pathogenesis of appendicitis is unclear. We evaluated whether exposure to air pollution was associated with an increased incidence of appendicitis.

Methods

We identified 5191 adults who had been admitted to hospital with appendicitis between Apr. 1, 1999, and Dec. 31, 2006. The air pollutants studied were ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and suspended particulate matter of less than 10 μ and less than 2.5 μ in diameter. We estimated the odds of appendicitis relative to short-term increases in concentrations of selected pollutants, alone and in combination, after controlling for temperature and relative humidity as well as the effects of age, sex and season.

Results

An increase in the interquartile range of the 5-day average of ozone was associated with appendicitis (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.03–1.25). In summer (July–August), the effects were most pronounced for ozone (OR 1.32, 95% CI 1.10–1.57), sulfur dioxide (OR 1.30, 95% CI 1.03–1.63), nitrogen dioxide (OR 1.76, 95% CI 1.20–2.58), carbon monoxide (OR 1.35, 95% CI 1.01–1.80) and particulate matter less than 10 μ in diameter (OR 1.20, 95% CI 1.05–1.38). We observed a significant effect of the air pollutants in the summer months among men but not among women (e.g., OR for increase in the 5-day average of nitrogen dioxide 2.05, 95% CI 1.21–3.47, among men and 1.48, 95% CI 0.85–2.59, among women). The double-pollutant model of exposure to ozone and nitrogen dioxide in the summer months was associated with attenuation of the effects of ozone (OR 1.22, 95% CI 1.01–1.48) and nitrogen dioxide (OR 1.48, 95% CI 0.97–2.24).

Interpretation

Our findings suggest that some cases of appendicitis may be triggered by short-term exposure to air pollution. If these findings are confirmed, measures to improve air quality may help to decrease rates of appendicitis.Appendicitis was introduced into the medical vernacular in 1886.¹ Since then, the prevailing theory of its pathogenesis implicated an obstruction of the appendiceal orifice by a fecalith or lymphoid hyperplasia.² However, this notion does not completely account for variations in incidence observed by age,^3,4 sex,^3,4 ethnic background,^3,4 family history,⁵ temporal–spatial clustering⁶ and seasonality,^3,4 nor does it completely explain the trends in incidence of appendicitis in developed and developing nations.^3,7,8The incidence of appendicitis increased dramatically in industrialized nations in the 19th century and in the early part of the 20th century.¹ Without explanation, it decreased in the middle and latter part of the 20th century.³ The decrease coincided with legislation to improve air quality. For example, after the United States Clean Air Act was passed in 1970,⁹ the incidence of appendicitis decreased by 14.6% from 1970 to 1984.³ Likewise, a 36% drop in incidence was reported in the United Kingdom between 1975 and 1994¹⁰ after legislation was passed in 1956 and 1968 to improve air quality and in the 1970s to control industrial sources of air pollution. Furthermore, appendicitis is less common in developing nations; however, as these countries become more industrialized, the incidence of appendicitis has been increasing.⁷Air pollution is known to be a risk factor for multiple conditions, to exacerbate disease states and to increase all-cause mortality.¹¹ It has a direct effect on pulmonary diseases such as asthma¹¹ and on nonpulmonary diseases including myocardial infarction, stroke and cancer.^11–13 Inflammation induced by exposure to air pollution contributes to some adverse health effects.^14–17 Similar to the effects of air pollution, a proinflammatory response has been associated with appendicitis.^18–20We conducted a case–crossover study involving a population-based cohort of patients admitted to hospital with appendicitis to determine whether short-term increases in concentrations of selected air pollutants were associated with hospital admission because of appendicitis.     

Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial

Background:Otitis media with effusion is a common problem that lacks an evidence-based nonsurgical treatment option. We assessed the clinical effectiveness of treatment with a nasal balloon device in a primary care setting.Methods:We conducted an open, pragmatic randomized controlled trial set in 43 family practices in the United Kingdom. Children aged 4–11 years with a recent history of ear symptoms and otitis media with effusion in 1 or both ears, confirmed by tympanometry, were allocated to receive either autoinflation 3 times daily for 1–3 months plus usual care or usual care alone. Clearance of middle-ear fluid at 1 and 3 months was assessed by experts masked to allocation.Results:Of 320 children enrolled, those receiving autoinflation were more likely than controls to have normal tympanograms at 1 month (47.3% [62/131] v. 35.6% [47/132]; adjusted relative risk [RR] 1.36, 95% confidence interval [CI] 0.99 to 1.88) and at 3 months (49.6% [62/125] v. 38.3% [46/120]; adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). Autoinflation produced greater improvements in ear-related quality of life (adjusted between-group difference in change from baseline in OMQ-14 [an ear-related measure of quality of life] score −0.42, 95% CI −0.63 to −0.22). Compliance was 89% at 1 month and 80% at 3 months. Adverse events were mild, infrequent and comparable between groups.Interpretation:Autoinflation in children aged 4–11 years with otitis media with effusion is feasible in primary care and effective both in clearing effusions and improving symptoms and ear-related child and parent quality of life. Trial registration: ISRCTN, No. 55208702.Otitis media with effusion, also known as glue ear, is an accumulation of fluid in the middle ear, without symptoms or signs of an acute ear infection. It is often associated with viral infection.^1–3 The prevalence rises to 46% in children aged 4–5 years,⁴ when hearing difficulty, other ear-related symptoms and broader developmental concerns often bring the condition to medical attention.^3,5,6 Middle-ear fluid is associated with conductive hearing losses of about 15–45 dB HL.⁷ Resolution is clinically unpredictable,^8–10 with about a third of cases showing recurrence.¹¹ In the United Kingdom, about 200 000 children with the condition are seen annually in primary care.^12,13 Research suggests some children seen in primary care are as badly affected as those seen in hospital.^7,9,14,15 In the United States, there were 2.2 million diagnosed episodes in 2004, costing an estimated $4.0 billion.¹⁶ Rates of ventilation tube surgery show variability between countries,^17–19 with a declining trend in the UK.²⁰Initial clinical management consists of reasonable temporizing or delay before considering surgery.¹³ Unfortunately, all available medical treatments for otitis media with effusion such as antibiotics, antihistamines, decongestants and intranasal steroids are ineffective and have unwanted effects, and therefore cannot be recommended.^21–23 Not only are antibiotics ineffective, but resistance to them poses a major threat to public health.^24,25 Although surgery is effective for a carefully selected minority,^13,26,27 a simple low-cost, nonsurgical treatment option could benefit a much larger group of symptomatic children, with the purpose of addressing legitimate clinical concerns without incurring excessive delays.Autoinflation using a nasal balloon device is a low-cost intervention with the potential to be used more widely in primary care, but current evidence of its effectiveness is limited to several small hospital-based trials²⁸ that found a higher rate of tympanometric resolution of ear fluid at 1 month.^29–31 Evidence of feasibility and effectiveness of autoinflation to inform wider clinical use is lacking.^13,28 Thus we report here the findings of a large pragmatic trial of the clinical effectiveness of nasal balloon autoinflation in a spectrum of children with clinically confirmed otitis media with effusion identified from primary care.     

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

Background

Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality.

Methods

A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death.

Results

Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7).

Interpretation

Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.Osteoporosis-related fractures are a major health concern, affecting a growing number of individuals worldwide. The burden of fracture has largely been assessed by the impact on health-related quality of life and health care costs.^1,2 Fractures can also be associated with death. However, trials that have examined the relation between fractures and mortality have had limitations that may influence their results and the generalizability of the studies, including small samples,^3,4 the examination of only 1 type of fracture,^4–10 the inclusion of only women,^8,11 the enrolment of participants from specific areas (i.e., hospitals or certain geographic regions),^{3,4,7,8,10,12} the nonrandom selection of participants^3–11 and the lack of statistical adjustment for confounding factors that may influence mortality.^3,5–7,12We evaluated the relation between incident fractures and mortality over a 5-year period in a cohort of men and women 50 years of age and older. In addition, we examined whether other characteristics of participants were risk factors for death.     

Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial

Background:

Little evidence exists on the effect of an energy-unrestricted healthy diet on metabolic syndrome. We evaluated the long-term effect of Mediterranean diets ad libitum on the incidence or reversion of metabolic syndrome.

Methods:

We performed a secondary analysis of the PREDIMED trial — a multicentre, randomized trial done between October 2003 and December 2010 that involved men and women (age 55–80 yr) at high risk for cardiovascular disease. Participants were randomly assigned to 1 of 3 dietary interventions: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts or advice on following a low-fat diet (the control group). The interventions did not include increased physical activity or weight loss as a goal. We analyzed available data from 5801 participants. We determined the effect of diet on incidence and reversion of metabolic syndrome using Cox regression analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results:

Over 4.8 years of follow-up, metabolic syndrome developed in 960 (50.0%) of the 1919 participants who did not have the condition at baseline. The risk of developing metabolic syndrome did not differ between participants assigned to the control diet and those assigned to either of the Mediterranean diets (control v. olive oil HR 1.10, 95% CI 0.94–1.30, p = 0.231; control v. nuts HR 1.08, 95% CI 0.92–1.27, p = 0.3). Reversion occurred in 958 (28.2%) of the 3392 participants who had metabolic syndrome at baseline. Compared with the control group, participants on either Mediterranean diet were more likely to undergo reversion (control v. olive oil HR 1.35, 95% CI 1.15–1.58, p < 0.001; control v. nuts HR 1.28, 95% CI 1.08–1.51, p < 0.001). Participants in the group receiving olive oil supplementation showed significant decreases in both central obesity and high fasting glucose (p = 0.02); participants in the group supplemented with nuts showed a significant decrease in central obesity.

Interpretation:

A Mediterranean diet supplemented with either extra virgin olive oil or nuts is not associated with the onset of metabolic syndrome, but such diets are more likely to cause reversion of the condition. An energy-unrestricted Mediterranean diet may be useful in reducing the risks of central obesity and hyperglycemia in people at high risk of cardiovascular disease. Trial registration: ClinicalTrials.gov, no. ISRCTN35739639.Metabolic syndrome is a cluster of 3 or more related cardiometabolic risk factors: central obesity (determined by waist circumference), hypertension, hypertriglyceridemia, low plasma high-density lipoprotein (HDL) cholesterol levels and hyperglycemia. Having the syndrome increases a person’s risk for type 2 diabetes and cardiovascular disease.^1,2 In addition, the condition is associated with increased morbidity and all-cause mortality.^1,3–5 The worldwide prevalence of metabolic syndrome in adults approaches 25%^6–8 and increases with age,⁷ especially among women,^8,9 making it an important public health issue.Several studies have shown that lifestyle modifications,¹⁰ such as increased physical activity,¹¹ adherence to a healthy diet^12,13 or weight loss,^14–16 are associated with reversion of the metabolic syndrome and its components. However, little information exists as to whether changes in the overall dietary pattern without weight loss might also be effective in preventing and managing the condition.The Mediterranean diet is recognized as one of the healthiest dietary patterns. It has shown benefits in patients with cardiovascular disease^17,18 and in the prevention and treatment of related conditions, such as diabetes,^19–21 hypertension^22,23 and metabolic syndrome.²⁴Several cross-sectional^25–29 and prospective^30–32 epidemiologic studies have suggested an inverse association between adherence to the Mediterranean diet and the prevalence or incidence of metabolic syndrome. Evidence from clinical trials has shown that an energy-restricted Mediterranean diet³³ or adopting a Mediterranean diet after weight loss³⁴ has a beneficial effect on metabolic syndrome. However, these studies did not determine whether the effect could be attributed to the weight loss or to the diets themselves.Seminal data from the PREDIMED (PREvención con DIeta MEDiterránea) study suggested that adherence to a Mediterranean diet supplemented with nuts reversed metabolic syndrome more so than advice to follow a low-fat diet.³⁵ However, the report was based on data from only 1224 participants followed for 1 year. We have analyzed the data from the final PREDIMED cohort after a median follow-up of 4.8 years to determine the long-term effects of a Mediterranean diet on metabolic syndrome.     

Effectiveness of interventions designed to reduce the use of imaging for low-back pain: a systematic review

Background:Rates of imaging for low-back pain are high and are associated with increased health care costs and radiation exposure as well as potentially poorer patient outcomes. We conducted a systematic review to investigate the effectiveness of interventions aimed at reducing the use of imaging for low-back pain.Methods:We searched MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials from the earliest records to June 23, 2014. We included randomized controlled trials, controlled clinical trials and interrupted time series studies that assessed interventions designed to reduce the use of imaging in any clinical setting, including primary, emergency and specialist care. Two independent reviewers extracted data and assessed risk of bias. We used raw data on imaging rates to calculate summary statistics. Study heterogeneity prevented meta-analysis.Results:A total of 8500 records were identified through the literature search. Of the 54 potentially eligible studies reviewed in full, 7 were included in our review. Clinical decision support involving a modified referral form in a hospital setting reduced imaging by 36.8% (95% confidence interval [CI] 33.2% to 40.5%). Targeted reminders to primary care physicians of appropriate indications for imaging reduced referrals for imaging by 22.5% (95% CI 8.4% to 36.8%). Interventions that used practitioner audits and feedback, practitioner education or guideline dissemination did not significantly reduce imaging rates. Lack of power within some of the included studies resulted in lack of statistical significance despite potentially clinically important effects.Interpretation:Clinical decision support in a hospital setting and targeted reminders to primary care doctors were effective interventions in reducing the use of imaging for low-back pain. These are potentially low-cost interventions that would substantially decrease medical expenditures associated with the management of low-back pain.Current evidence-based clinical practice guidelines recommend against the routine use of imaging in patients presenting with low-back pain.^1–3 Despite this, imaging rates remain high,^4,5 which indicates poor concordance with these guidelines.^6,7Unnecessary imaging for low-back pain has been associated with poorer patient outcomes, increased radiation exposure and higher health care costs.⁸ No short- or long-term clinical benefits have been shown with routine imaging of the low back, and the diagnostic value of incidental imaging findings remains uncertain.^9–12 A 2008 systematic review found that imaging accounted for 7% of direct costs associated with low-back pain, which in 1998 translated to more than US$6 billion in the United States and £114 million in the United Kingdom.¹³ Current costs are likely to be substantially higher, with an estimated 65% increase in spine-related expenditures between 1997 and 2005.¹⁴Various interventions have been tried for reducing imaging rates among people with low-back pain. These include strategies targeted at the practitioner such as guideline dissemination,^15–17 education workshops,^18,19 audit and feedback of imaging use,^7,20,21 ongoing reminders⁷ and clinical decision support.^22–24 It is unclear which, if any, of these strategies are effective.²⁵ We conducted a systematic review to investigate the effectiveness of interventions designed to reduce imaging rates for the management of low-back pain.     

Effectiveness of training family physicians to deliver a brief intervention to address excessive substance use among young patients: a cluster randomized controlled trial

Background:

Brief interventions delivered by family physicians to address excessive alcohol use among adult patients are effective. We conducted a study to determine whether such an intervention would be similarly effective in reducing binge drinking and excessive cannabis use among young people.

Methods:

We conducted a cluster randomized controlled trial involving 33 family physicians in Switzerland. Physicians in the intervention group received training in delivering a brief intervention to young people during the consultation in addition to usual care. Physicians in the control group delivered usual care only. Consecutive patients aged 15–24 years were recruited from each practice and, before the consultation, completed a confidential questionnaire about their general health and substance use. Patients were followed up at 3, 6 and 12 months after the consultation. The primary outcome measure was self-reported excessive substance use (≥ 1 episode of binge drinking, or ≥ 1 joint of cannabis per week, or both) in the past 30 days.

Results:

Of the 33 participating physicians, 17 were randomly allocated to the intervention group and 16 to the control group. Of the 594 participating patients, 279 (47.0%) identified themselves as binge drinkers or excessive cannabis users, or both, at baseline. Excessive substance use did not differ significantly between patients whose physicians were in the intervention group and those whose physicians were in the control group at any of the follow-up points (odds ratio [OR] and 95% confidence interval [CI] at 3 months: 0.9 [0.6–1.4]; at 6 mo: 1.0 [0.6–1.6]; and at 12 mo: 1.1 [0.7–1.8]). The differences between groups were also nonsignificant after we re stricted the analysis to patients who reported excessive substance use at baseline (OR 1.6, 95% CI 0.9–2.8, at 3 mo; OR 1.7, 95% CI 0.9–3.2, at 6 mo; and OR 1.9, 95% CI 0.9–4.0, at 12 mo).

Interpretation:

Training family physicians to use a brief intervention to address excessive substance use among young people was not effective in reducing binge drinking and excessive cannabis use in this patient population. Trial registration: Australian New Zealand Clinical Trials Registry, no. ACTRN12608000432314.Most health-compromising behaviours begin in adolescence.¹ Interventions to address these behaviours early are likely to bring long-lasting benefits.² Harmful use of alcohol is a leading factor associated with premature death and disability worldwide, with a disproportionally high impact on young people (aged 10–24 yr).^3,4 Similarly, early cannabis use can have adverse consequences that extend into adulthood.^5–8In adolescence and early adulthood, binge drinking on at least a monthly basis is associated with an increased risk of adverse outcomes later in life.^9–12 Although any cannabis use is potentially harmful, weekly use represents a threshold in adolescence related to an increased risk of cannabis (and tobacco) dependence in adulthood.¹³ Binge drinking affects 30%–50% and excessive cannabis use about 10% of the adolescent and young adult population in Europe and the United States.^10,14,15Reducing substance-related harm involves multisectoral approaches, including promotion of healthy child and adolescent development, regulatory policies and early treatment interventions.¹⁶ Family physicians can add to the public health messages by personalizing their content within brief interventions.^17,18 There is evidence that brief interventions can encourage young people to reduce substance use, yet most studies have been conducted in community settings (mainly educational), emergency services or specialized addiction clinics.^1,16 Studies aimed at adult populations have shown favourable effects of brief alcohol interventions, and to some extent brief cannabis interventions, in primary care.^19–22 These interventions have been recommended for adolescent populations.^4,5,16 Yet young people have different modes of substance use and communication styles that may limit the extent to which evidence from adult studies can apply to them.Recently, a systematic review of brief interventions to reduce alcohol use in adolescents identified only 1 randomized controlled trial in primary care.²³ The tested intervention, not provided by family physicians but involving audio self-assessment, was ineffective in reducing alcohol use in exposed adolescents.²⁴ Sanci and colleagues showed that training family physicians to address health-risk behaviours among adolescents was effective in improving provider performance, but the extent to which this translates into improved outcomes remains unknown.^25,26 Two nonrandomized studies suggested screening for substance use and brief advice by family physicians could favour reduced alcohol and cannabis use among adolescents,^27,28 but evidence from randomized trials is lacking.²⁹We conducted the PRISM-Ado (Primary care Intervention Addressing Substance Misuse in Adolescents) trial, a cluster randomized controlled trial of the effectiveness of training family physicians to deliver a brief intervention to address binge drinking and excessive cannabis use among young people.     

Risk of vascular events in patients with polymyalgia rheumatica

Background:

Polymyalgia rheumatica is one of the most common inflammatory rheumatologic conditions in older adults. Other inflammatory rheumatologic disorders are associated with an excess risk of vascular disease. We investigated whether polymyalgia rheumatica is associated with an increased risk of vascular events.

Methods:

We used the General Practice Research Database to identify patients with a diagnosis of incident polymyalgia rheumatica between Jan. 1, 1987, and Dec. 31, 1999. Patients were matched by age, sex and practice with up to 5 patients without polymyalgia rheumatica. Patients were followed until their first vascular event (cardiovascular, cerebrovascular, peripheral vascular) or the end of available records (May 2011). All participants were free of vascular disease before the diagnosis of polymyalgia rheumatica (or matched date). We used Cox regression models to compare time to first vascular event in patients with and without polymyalgia rheumatica.

Results:

A total of 3249 patients with polymyalgia rheumatica and 12 735 patients without were included in the final sample. Over a median follow-up period of 7.8 (interquartile range 3.3–12.4) years, the rate of vascular events was higher among patients with polymyalgia rheumatica than among those without (36.1 v. 12.2 per 1000 person-years; adjusted hazard ratio 2.6, 95% confidence interval 2.4–2.9). The increased risk of a vascular event was similar for each vascular disease end point. The magnitude of risk was higher in early disease and in patients younger than 60 years at diagnosis.

Interpretation:

Patients with polymyalgia rheumatica have an increased risk of vascular events. This risk is greatest in the youngest age groups. As with other forms of inflammatory arthritis, patients with polymyalgia rheumatica should have their vascular risk factors identified and actively managed to reduce this excess risk.Inflammatory rheumatologic disorders such as rheumatoid arthritis,^1,2 systemic lupus erythematosus,^2,3 gout,⁴ psoriatic arthritis^2,5 and ankylosing spondylitis^2,6 are associated with an increased risk of vascular disease, especially cardiovascular disease, leading to substantial morbidity and premature death.^2–6 Recognition of this excess vascular risk has led to management guidelines advocating screening for and management of vascular risk factors.^7–9Polymyalgia rheumatica is one of the most common inflammatory rheumatologic conditions in older adults,¹⁰ with a lifetime risk of 2.4% for women and 1.7% for men.¹¹ To date, evidence regarding the risk of vascular disease in patients with polymyalgia rheumatica is unclear. There are a number of biologically plausible mechanisms between polymyalgia rheumatica and vascular disease. These include the inflammatory burden of the disease,^12,13 the association of the disease with giant cell arteritis (causing an inflammatory vasculopathy, which may lead to subclinical arteritis, stenosis or aneurysms),¹⁴ and the adverse effects of long-term corticosteroid treatment (e.g., diabetes, hypertension and dyslipidemia).^15,16 Paradoxically, however, use of corticosteroids in patients with polymyalgia rheumatica may actually decrease vascular risk by controlling inflammation.¹⁷ A recent systematic review concluded that although some evidence exists to support an association between vascular disease and polymyalgia rheumatica,¹⁸ the existing literature presents conflicting results, with some studies reporting an excess risk of vascular disease^19,20 and vascular death,^21,22 and others reporting no association.^23–26 Most current studies are limited by poor methodologic quality and small samples, and are based on secondary care cohorts, who may have more severe disease, yet most patients with polymyalgia rheumatica receive treatment exclusively in primary care.²⁷The General Practice Research Database (GPRD), based in the United Kingdom, is a large electronic system for primary care records. It has been used as a data source for previous studies,²⁸ including studies on the association of inflammatory conditions with vascular disease²⁹ and on the epidemiology of polymyalgia rheumatica in the UK.³⁰ The aim of the current study was to examine the association between polymyalgia rheumatica and vascular disease in a primary care population.     

Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial

Background

Cryotherapy is widely used for the treatment of cutaneous warts in primary care. However, evidence favours salicylic acid application. We compared the effectiveness of these treatments as well as a wait-and-see approach.

Methods

Consecutive patients with new cutaneous warts were recruited in 30 primary care practices in the Netherlands between May 1, 2006, and Jan. 26, 2007. We randomly allocated eligible patients to one of three groups: cryotherapy with liquid nitrogen every two weeks, self-application of salicylic acid daily or a wait-and-see approach. The primary outcome was the proportion of participants whose warts were all cured at 13 weeks. Analysis was on an intention-to-treat basis. Secondary outcomes included treatment adherence, side effects and treatment satisfaction. Research nurses assessed outcomes during home visits at 4, 13 and 26 weeks.

Results

Of the 250 participants (age 4 to 79 years), 240 were included in the analysis at 13 weeks (loss to follow-up 4%). Cure rates were 39% (95% confidence interval [CI] 29%–51%) in the cryotherapy group, 24% (95% CI 16%–35%) in the salicylic acid group and 16% (95% CI 9.5%–25%) in the wait-and-see group. Differences in effectiveness were most pronounced among participants with common warts (n = 116): cure rates were 49% (95% CI 34%–64%) in the cryotherapy group, 15% (95% CI 7%–30%) in the salicylic acid group and 8% (95% CI 3%–21%) in the wait-and-see group. Cure rates among the participants with plantar warts (n = 124) did not differ significantly between treatment groups.

Interpretation

For common warts, cryotherapy was the most effective therapy in primary care. For plantar warts, we found no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait-and-see approach after 13 weeks. (ClinicalTrial.gov registration no. ISRCTN42730629)Cutaneous warts are common.^1–3 Up to one-third of primary school children have warts, of which two-thirds resolve within two years.^4,5 Because warts frequently result in discomfort,⁶ 2% of the general population and 6% of school-aged children each year present with warts to their family physician.^7,8 The usual treatment is cryotherapy with liquid nitrogen or, less frequently, topical application of salicylic acid.^9–12 Some physicians choose a wait-and-see approach because of the benign natural course of warts and the risk of side effects of treatment.^10,11A recent Cochrane review on treatments of cutaneous warts concluded that available studies were small, poorly designed or limited to dermatology outpatients.^10,11 Evidence on cryotherapy was contradictory,^13–18 whereas the evidence on salicylic acid was more convincing.^19–23 However, studies that compared cryotherapy and salicylic acid directly showed no differences in effectiveness.^24,25 The Cochrane review called for high-quality trials in primary care to compare the effects of cryotherapy, salicylic acid and placebo.We conducted a three-arm randomized controlled trial to compare the effectiveness of cryotherapy with liquid nitrogen, topical application of salicylic acid and a wait-and-see approach for the treatment of common and plantar warts in primary care.     

Incidence and causes of heparin-induced skin lesions

Background

Little is known about the incidence and causes of heparin-induced skin lesions. The 2 most commonly reported causes of heparin-induced skin lesions are immune-mediated heparin-induced thrombocytopenia and delayed-type hypersensitivity reactions.

Methods

We prospectively examined consecutive patients who received subcutaneous heparin (most often enoxaparin or nadroparin) for the presence of heparin-induced skin lesions. If such lesions were identified, we performed a skin biopsy, platelet count measurements, and antiplatelet-factor 4 antibody and allergy testing.

Results

We enrolled 320 patients. In total, 24 patients (7.5%, 95% confidence interval [CI] 4.7%–10.6%) had heparin-induced skin lesions. Delayed-type hypersensitivity reactions were identified as the cause in all 24 patients. One patient with histopathologic evidence of delayed-type hypersensitivity tested positive for antiplatelet-factor 4 antibodies. We identified the following risk factors for heparin-induced skin lesions: a body mass index greater than 25 (odds ratio [OR] 4.6, 95% CI 1.7–15.3), duration of heparin therapy longer than 9 days (OR 5.9, 95% CI 1.9–26.3) and female sex (OR 3.0, 95% CI 1.1–8.8).

Interpretation

Heparin-induced skin lesions are relatively common, have identifiable risk factors and are commonly caused by a delayed-type hypersensitivity reaction (type IV allergic response). (ClinicalTrials.gov trial register no. {"type":"clinical-trial","attrs":{"text":"NCT00510432","term_id":"NCT00510432"}}NCT00510432.)Hpeparin has been used as an anticoagulant for over 60 years.¹ Well-known adverse effects of heparin therapy are bleeding, osteoporosis, hair loss, and immune and nonimmune heparin-induced thrombocytopenia. The incidence of heparin-induced skin lesions is unknown, despite being increasingly reported.^2–4 Heparin-induced skin lesions may be caused by at least 5 mechanisms: delayed-type (type IV) hypersensitivity responses,^2,4–6 immune-mediated thrombocytopenia,³ type I allergic reactions,^7,8 skin necrosis⁹ and pustulosis.¹⁰Heparin-induced skin lesions may indicate the presence of life-threatening heparin-induced thrombocytopenia¹¹ — even in the absence of thrombocytopenia.³ There are no data available on the incidence of heparin-induced skin lesions or their causes. Given the rising number of reports of heparin-induced skin lesions and the importance of correctly diagnosing this condition, we sought to determine the incidence of heparin-induced skin lesions.     

Prevalence of and risk factors for persistent postoperative nonanginal pain after cardiac surgery: a 2-year prospective multicentre study

Background:

Persistent postoperative pain continues to be an underrecognized complication. We examined the prevalence of and risk factors for this type of pain after cardiac surgery.

Methods:

We enrolled patients scheduled for coronary artery bypass grafting or valve replacement, or both, from Feb. 8, 2005, to Sept. 1, 2009. Validated measures were used to assess (a) preoperative anxiety and depression, tendency to catastrophize in the face of pain, health-related quality of life and presence of persistent pain; (b) pain intensity and interference in the first postoperative week; and (c) presence and intensity of persistent postoperative pain at 3, 6, 12 and 24 months after surgery. The primary outcome was the presence of persistent postoperative pain during 24 months of follow-up.

Results:

A total of 1247 patients completed the preoperative assessment. Follow-up retention rates at 3 and 24 months were 84% and 78%, respectively. The prevalence of persistent postoperative pain decreased significantly over time, from 40.1% at 3 months to 22.1% at 6 months, 16.5% at 12 months and 9.5% at 24 months; the pain was rated as moderate to severe in 3.6% at 24 months. Acute postoperative pain predicted both the presence and severity of persistent postoperative pain. The more intense the pain during the first week after surgery and the more it interfered with functioning, the more likely the patients were to report persistent postoperative pain. Pre-existing persistent pain and increased preoperative anxiety also predicted the presence of persistent postoperative pain.

Interpretation:

Persistent postoperative pain of nonanginal origin after cardiac surgery affected a substantial proportion of the study population. Future research is needed to determine whether interventions to modify certain risk factors, such as preoperative anxiety and the severity of pain before and immediately after surgery, may help to minimize or prevent persistent postoperative pain.Postoperative pain that persists beyond the normal time for tissue healing (> 3 mo) is increasingly recognized as an important complication after various types of surgery and can have serious consequences on patients’ daily living.^1–3 Cardiac surgeries, such as coronary artery bypass grafting (CABG) and valve replacement, rank among the most frequently performed interventions worldwide.⁴ They aim to improve survival and quality of life by reducing symptoms, including anginal pain. However, persistent postoperative pain of nonanginal origin has been reported in 7% to 60% of patients following these surgeries.^5–23 Such variability is common in other types of major surgery and is due mainly to differences in the definition of persistent postoperative pain, study design, data collection methods and duration of follow-up.^1–3,24Few prospective cohort studies have examined the exact time course of persistent postoperative pain after cardiac surgery, and follow-up has always been limited to a year or less.^9,14,25 Factors that put patients at risk of this type of problem are poorly understood.²⁶ Studies have reported inconsistent results regarding the contribution of age, sex, body mass index, preoperative angina, surgical technique, grafting site, postoperative complications or level of opioid consumption after surgery.^{5–7,9,13,14,16–19,21–23,25,27} Only 1 study investigated the role of chronic nonanginal pain before surgery as a contributing factor;²¹ 5 others prospectively assessed the association between persistent postoperative pain and acute pain intensity in the first postoperative week but reported conflicting results.^{13,14,21,22,25} All of the above studies were carried out in a single hospital and included relatively small samples. None of the studies examined the contribution of psychological factors such as levels of anxiety and depression before cardiac surgery, although these factors have been shown to influence acute or persistent postoperative pain in other types of surgery.^1,24,28,29We conducted a prospective multicentre cohort study (the CARD-PAIN study) to determine the prevalence of persistent postoperative pain of nonanginal origin up to 24 months after cardiac surgery and to identify risk factors for the presence and severity of the condition.     

Diagnostic accuracy of level 3 portable sleep tests versus level 1 polysomnography for sleep-disordered breathing: a systematic review and meta-analysis

Background:

Greater awareness of sleep-disordered breathing and rising obesity rates have fueled demand for sleep studies. Sleep testing using level 3 portable devices may expedite diagnosis and reduce the costs associated with level 1 in-laboratory polysomnography. We sought to assess the diagnostic accuracy of level 3 testing compared with level 1 testing and to identify the appropriate patient population for each test.

Methods:

We conducted a systematic review and meta-analysis of comparative studies of level 3 versus level 1 sleep tests in adults with suspected sleep-disordered breathing. We searched 3 research databases and grey literature sources for studies that reported on diagnostic accuracy parameters or disease management after diagnosis. Two reviewers screened the search results, selected potentially relevant studies and extracted data. We used a bivariate mixed-effects binary regression model to estimate summary diagnostic accuracy parameters.

Results:

We included 59 studies involving a total of 5026 evaluable patients (mostly patients suspected of having obstructive sleep apnea). Of these, 19 studies were included in the meta-analysis. The estimated area under the receiver operating characteristics curve was high, ranging between 0.85 and 0.99 across different levels of disease severity. Summary sensitivity ranged between 0.79 and 0.97, and summary specificity ranged between 0.60 and 0.93 across different apnea–hypopnea cut-offs. We saw no significant difference in the clinical management parameters between patients who underwent either test to receive their diagnosis.

Interpretation:

Level 3 portable devices showed good diagnostic performance compared with level 1 sleep tests in adult patients with a high pretest probability of moderate to severe obstructive sleep apnea and no unstable comorbidities. For patients suspected of having other types of sleep-disordered breathing or sleep disorders not related to breathing, level 1 testing remains the reference standard.Undiagnosed sleep-disordered breathing places a substantial burden on patients, families, health care systems and society.¹ Sleep fragmentation and recurrent hypoxemia cause daytime sleepiness and impaired concentration, which increase the risk of motor vehicle collisions and occupational accidents.^2–7 In addition, sleep-disordered breathing is associated with hypertension, stroke, cardiovascular disease, obesity and type 2 diabetes,^8–12 all of which involve greater use of health care resources.^13–17Obstructive sleep apnea is the most common type of sleep-disordered breathing. Narrowing of the upper airway during inspiration results in episodes of apnea (breathing cessation for at least 10 seconds), hypopnea (reduced airflow), oxygen desaturation and arousal from sleep due to respiratory effort.¹⁸ Clinical signs and symptoms include snoring, reports of nocturnal apnea, gasping or choking witnessed by a partner, daytime sleepiness, morning headaches and inability to concentrate. Patients with obesity or cardiovascular disease are at increased risk.¹⁹The severity of obstructive sleep apnea is usually graded using the apnea–hypopnea index (the mean number of apneas and hypopneas per hour of sleep) as follows: mild (5–14), moderate (15–29) and severe (≥ 30).^18,20Other, less common types of sleep-disordered breathing include upper airway resistance syndrome, obesity hyperventilation syndrome, central sleep apnea, and nocturnal hypoventilation/hypoxemia secondary to cardiopulmonary or neuromuscular disease. It is not uncommon for patients to have more than 1 type of sleep-disordered breathing.Estimates of the prevalence of sleep-disordered breathing vary depending on the population (e.g., by sex, age and comorbidities).²¹ According to the Wisconsin Sleep Cohort Study, values in American adults (aged 30–60 yr) are 24% for men and 9% for women.¹ A Canadian survey found a self-reported prevalence of sleep apnea of 3% among adults more than 18 years of age, and 5% among those more than 45 years of age.²² As the population ages and rates of obesity increase, the prevalence of sleep-disordered breathing is climbing.^1,19,23,24 Given its clinical implications, accurate diagnosis and treatment of the condition are critical.Level 1 sleep testing, or polysomnography, requires an overnight stay in a sleep laboratory with a technician in attendance. It captures a minimum of 7 channels of data (but typically ≥ 16), including respiratory, cardiovascular and neurologic parameters, to produce a comprehensive picture of sleep architecture. Level 1 is considered the reference standard for diagnosing all types of sleep-disordered breathing and sleep disorders.^19,25–27 However, limited facilities and the growing demand for sleep studies have resulted in long wait times.²⁸ Level 2 sleep testing uses level 1 equipment, but is performed without a technician in attendance.Level 3 testing uses portable monitors that allow sleep studies to be done at the patient’s home or elsewhere. This option was introduced as a more accessible and less expensive alternative to in-laboratory polysomnography. Level 3 devices record at least 3 channels of data (e.g., oximetry, airflow, respiratory effort). Unlike level 1, level 3 testing cannot measure the duration of sleep, the number of arousals or sleep stages, nor can it detect nonrespiratory sleep disorders.^27,29 Level 4 devices are also portable, but they capture less data — usually only 1 or 2 channels.^27,30We conducted a systematic review and meta-analysis to compare the diagnostic accuracy of the widely used level 3 portable monitors to in-laboratory polysomnography, and to determine the subpopulations of patients whose conditions might be most appropriately diagnosed with each test.     

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule

Background

Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care.

Methods

We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort).

Results

The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83–0.91) for the derivation cohort and 0.90 (95% CI 0.87–0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3–5 points; negative result ≤ 2 points), which had a sensitivity of 87.1% (95% CI 79.9%–94.2%) and a specificity of 80.8% (77.6%–83.9%).

Interpretation

The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care.Chest pain is common. Studies have shown a lifetime prevalence of 20% to 40% in the general population.¹ Its prevalence in primary care ranges from 0.7% to 2.7% depending on inclusion criteria and country,^2–4 with coronary artery disease being the underlying cause in about 12% of primary care patients.^1,5 General practitioners are challenged to identify serious cardiac disease reliably and also protect patients from unnecessary investigations and hospital admissions. Because electrocardiography and the cardiac troponin test are of limited value in primary care,^6,7 history taking and physical examination remain the main diagnostic tools.Most published studies on the diagnostic accuracy of signs and symptoms for acute coronary events have been conducted in high-prevalence settings such as hospital emergency departments.^8–10 Predictive scores have also been developed for use in emergency departments, mainly for the diagnosis of acute coronary syndromes.^11–13 To what degree these apply in primary care is unknown.^14–16A clinical prediction score to rule out coronary artery disease in general practice has been developed.¹⁷ However, it did not perform well when validated externally. The aim of our study was to develop a simple, valid and usable prediction score based on signs and symptoms to help primary care physicians rule out coronary artery disease in patients presenting with chest pain.     

Utility of prior screening for methicillin-resistant Staphylococcus aureus in predicting resistance of S. aureus infections

Background:

Screening for methicillin-resistant Staphylococcus aureus (MRSA) is intended to reduce nosocomial spread by identifying patients colonized by MRSA. Given the widespread use of this screening, we evaluated its potential clinical utility in predicting the resistance of clinical isolates of S. aureus.

Methods:

We conducted a 2-year retrospective cohort study that included patients with documented clinical infection with S. aureus and prior screening for MRSA. We determined test characteristics, including sensitivity and specificity, of screening for predicting the resistance of subsequent S. aureus isolates.

Results:

Of 510 patients included in the study, 53 (10%) had positive results from MRSA screening, and 79 (15%) of infecting isolates were resistant to methicillin. Screening for MRSA predicted methicillin resistance of the infecting isolate with 99% (95% confidence interval [CI] 98%–100%) specificity and 63% (95% CI 52%–74%) sensitivity. When screening swabs were obtained within 48 hours before isolate collection, sensitivity increased to 91% (95% CI 71%–99%) and specificity was 100% (95% CI 97%–100%), yielding a negative likelihood ratio of 0.09 (95% CI 0.01–0.3) and a negative predictive value of 98% (95% CI 95%–100%). The time between swab and isolate collection was a significant predictor of concordance of methicillin resistance in swabs and isolates (odds ratio 6.6, 95% CI 1.6–28.2).

Interpretation:

A positive result from MRSA screening predicted methicillin resistance in a culture-positive clinical infection with S. aureus. Negative results on MRSA screening were most useful for excluding methicillin resistance of a subsequent infection with S. aureus when the screening swab was obtained within 48 hours before collection of the clinical isolate.Antimicrobial resistance is a global problem. The prevalence of resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), has reached high levels in many countries.^1–3 Methicillin resistance in S. aureus is associated with excess mortality, hospital stays and health care costs,^3,4 possibly owing to increased virulence or less effective treatments for MRSA compared with methicillin-sensitive S. aureus (MSSA).⁵The initial selection of appropriate empirical antibiotic treatment affects mortality, morbidity and potential health care expenditures.^6–8 The optimal choice of antibiotics in S. aureus infections is important for 3 major reasons: β-lactam antibiotics have shown improved efficacy over vancomycin and are the ideal treatment for susceptible strains of S. aureus;⁶ β-lactam antibiotics are ineffective against MRSA, and so vancomycin or other newer agents must be used empirically when MRSA is suspected; and unnecessary use of broad-spectrum antibiotics (e.g., vancomycin) can lead to the development of further antimicrobial resistance.⁹ It is therefore necessary to make informed decisions regarding selection of empirical antibiotics.^10–13 Consideration of a patient’s previous colonization status is important, because colonization predates most hospital and community-acquired infections.^10,14Universal or targeted surveillance for MRSA has been implemented widely as a means of limiting transmission of this antibiotic-resistant pathogen.^15,16 Although results of MRSA screening are not intended to guide empirical treatment, they may offer an additional benefit among patients in whom clinical infection with S. aureus develops.Studies that examined the effects of MRSA carriage on the subsequent likelihood of infection allude to the potential diagnostic benefit of prior screening for MRSA.^17,18 Colonization by MRSA at the time of hospital admission is associated with a 13-fold increased risk of subsequent MRSA infection.^17,18 Moreover, studies that examined nasal carriage of S. aureus after documented S. aureus bacteremia have shown remarkable concordance between the genotypes of paired colonizing and invasive strains (82%–94%).^19,20 The purpose of our study was to identify the usefulness of prior screening for MRSA for predicting methicillin resistance in culture-positive S. aureus infections.     

Risk of suicide after a concussion

Background:Head injuries have been associated with subsequent suicide among military personnel, but outcomes after a concussion in the community are uncertain. We assessed the long-term risk of suicide after concussions occurring on weekends or weekdays in the community.Methods:We performed a longitudinal cohort analysis of adults with diagnosis of a concussion in Ontario, Canada, from Apr. 1, 1992, to Mar. 31, 2012 (a 20-yr period), excluding severe cases that resulted in hospital admission. The primary outcome was the long-term risk of suicide after a weekend or weekday concussion.Results:We identified 235 110 patients with a concussion. Their mean age was 41 years, 52% were men, and most (86%) lived in an urban location. A total of 667 subsequent suicides occurred over a median follow-up of 9.3 years, equivalent to 31 deaths per 100 000 patients annually or 3 times the population norm. Weekend concussions were associated with a one-third further increased risk of suicide compared with weekday concussions (relative risk 1.36, 95% confidence interval 1.14–1.64). The increased risk applied regardless of patients’ demographic characteristics, was independent of past psychiatric conditions, became accentuated with time and exceeded the risk among military personnel. Half of these patients had visited a physician in the last week of life.Interpretation:Adults with a diagnosis of concussion had an increased long-term risk of suicide, particularly after concussions on weekends. Greater attention to the long-term care of patients after a concussion in the community might save lives because deaths from suicide can be prevented.Suicide is a leading cause of death in both military and community settings.¹ During 2010, 3951 suicide deaths occurred in Canada² and 38 364 in the United States.³ The frequency of attempted suicide is about 25 times higher, and the financial costs in the US equate to about US$40 billion annually.⁴ The losses from suicide in Canada are comparable to those in other countries when adjusted for population size.⁵ Suicide deaths can be devastating to surviving family and friends.⁶ Suicide in the community is almost always related to a psychiatric illness (e.g., depression, substance abuse), whereas suicide in the military is sometimes linked to a concussion from combat injury.^7–10Concussion is the most common brain injury in young adults and is defined as a transient disturbance of mental function caused by acute trauma.¹¹ About 4 million concussion cases occur in the US each year, equivalent to a rate of about 1 per 1000 adults annually;¹² direct Canadian data are not available. The majority lead to self-limited symptoms, and only a small proportion have a protracted course.¹³ However, the frequency of depression after concussion can be high,^14,15 and traumatic brain injury in the military has been associated with subsequent suicide.^8,16 Severe head trauma resulting in admission to hospital has also been associated with an increased risk of suicide, whereas mild concussion in ambulatory adults is an uncertain risk factor.^17–20The aim of this study was to determine whether concussion was associated with an increased long-term risk of suicide and, if so, whether the day of the concussion (weekend v. weekday) could be used to identify patients at further increased risk. The severity and mechanism of injury may differ by day of the week because recreational injuries are more common on weekends and occupational injuries are more common on weekdays.^21–27 The risk of a second concussion, use of protective safeguards, propensity to seek care, subsequent oversight, sense of responsibility and other nuances may also differ for concussions acquired from weekend recreation rather than weekday work.^28–31 Medical care on weekends may also be limited because of shortfalls in staffing.³²     

Cancer risk related to low-dose ionizing radiation from cardiac imaging in patients after acute myocardial infarction

Background

Patients exposed to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction may be at increased risk of cancer.

Methods

Using an administrative database, we selected a cohort of patients who had an acute myocardial infarction between April 1996 and March 2006 and no history of cancer. We documented all cardiac imaging and therapeutic procedures involving low-dose ionizing radiation. The primary outcome was risk of cancer. Statistical analyses were performed using a time-dependent Cox model adjusted for age, sex and exposure to low-dose ionizing radiation from noncardiac imaging to account for work-up of cancer.

Results

Of the 82 861 patients included in the cohort, 77% underwent at least one cardiac imaging or therapeutic procedure involving low-dose ionizing radiation in the first year after acute myocardial infarction. The cumulative exposure to radiation from cardiac procedures was 5.3 milliSieverts (mSv) per patient-year, of which 84% occurred during the first year after acute myocardial infarction. A total of 12 020 incident cancers were diagnosed during the follow-up period. There was a dose-dependent relation between exposure to radiation from cardiac procedures and subsequent risk of cancer. For every 10 mSv of low-dose ionizing radiation, there was a 3% increase in the risk of age- and sex-adjusted cancer over a mean follow-up period of five years (hazard ratio 1.003 per milliSievert, 95% confidence interval 1.002–1.004).

Interpretation

Exposure to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction is associated with an increased risk of cancer.Studies involving atomic bomb survivors have documented an increased incidence of malignant neoplasm related to the radiation exposure.^1–4 Survivors who were farther from the epicentre of the blast had a lower incidence of cancer, whereas those who were closer had a higher incidence.⁵ Similar risk estimates have been reported among workers in nuclear plants.⁶ However, little is known about the relation between exposure to low-dose ionizing radiation from medical procedures and the risk of cancer.In the past six decades since the atomic bomb explosions, most individuals worldwide have had minimal exposure to ionizing radiation. However, the recent increase in the use of medical imaging and therapeutic procedures involving low-dose ionizing radiation has led to a growing concern that individual patients may be at increased risk of cancer.^7–12 Whereas strict regulatory control is placed on occupational exposure at work sites, no such control exists among patients who are exposed to such radiation.^13–16It is not only the frequency of these procedures that is increasing. Newer types of imaging procedures are using higher doses of low-dose ionizing radiation than those used with more traditional procedures.^8,11 Among patients being evaluated for coronary artery disease, for example, coronary computed tomography is increasingly being used. This test may be used in addition to other tests such as nuclear scans, coronary angiography and percutaneous coronary intervention, each of which exposes the patient to low-dose ionizing radiation.^12,17–21 Imaging procedures provide information that can be used to predict the prognosis of patients with coronary artery disease. Since such predictions do not necessarily translate into better clinical outcomes,^8,12 the prognostic value obtained from imaging procedures using low-dose ionizing radiation needs to be balanced against the potential for risk.Authors of several studies have estimated that the risk of cancer is not negligible among patients exposed to low-dose ionizing radiation.^22–27 To our knowledge, none of these studies directly linked cumulative exposure and cancer risk. We examined a cohort of patients who had acute myocardial infarction and measured the association between low-dose ionizing radiation from cardiac imaging and therapeutic procedures and the risk of cancer.     

Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis

Background

Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association.

Methods

We searched three electronic databases (MEDLINE [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect.

Results

We identified 31 studies: five case–control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11–1.46, I² 90.5%) and histamine₂ receptor antagonists (adjusted OR 1.22, 95% CI 1.09–1.36, I² 0.0%). In the randomized controlled trials, use of histamine₂ receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01–1.48, I² 30.6%).

Interpretation

Use of a proton pump inhibitor or histamine₂ receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.Recently, the medical literature has paid considerable attention to unrecognized adverse effects of commonly used medications and their potential public health impact.¹ One group of medications in widespread use is acid-suppressive drugs, which represent the second leading category of medication worldwide, with sales totalling US$26.9 billion in 2005.²Over the past 40 years, the development of potent acid-suppressive drugs, including proton pump inhibitors, has led to considerable improvements in the treatment of acid-related disorders of the upper gastrointestinal tract.³ Experts have generally viewed proton pump inhibitors as safe.⁴ However, potential complications such as gastrointestinal neoplasia, malabsorption of nutrients and increased susceptibility to infection have caused concern.⁵Of special interest is the possibility that acid-suppressive drugs could increase susceptibility to respiratory infections because these drugs increase gastric pH, thus allowing bacterial colonization.^6,7 Several previous studies have shown that treatment with acid-suppressive drugs might be associated with an increased risk of respiratory tract infections⁸ and community-acquired pneumonia in adults^6,7 and children.⁹ However, the association between use of acid-suppressive drugs and risk of pneumonia has been inconsistent.^10–13Given the widespread use of proton pump inhibitors and histamine₂ receptor antagonists, clarifying the potential impact of acid-suppressive therapy on the risk of pneumonia is of great importance to public health.¹⁴ Previous meta-analyses have focused on the role of acid-suppressive drugs in preventing stress ulcer,^11,13,15 but none have examined pneumonia as the primary outcome.The aim of this study was to summarize the association between the use of acid-suppressive drugs and the risk of pneumonia in observational studies and randomized controlled trials.