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1.  Association of Fluid Retention With Anemia and Clinical Outcomes Among Patients With Chronic Kidney Disease 
Observational studies have demonstrated an association between anemia and adverse outcomes in patients with chronic kidney disease (CKD). However, randomized trials failed to identify a benefit of higher hemoglobin concentrations, suggesting that the anemia‐outcome association may be confounded by unknown factors.
Methods and Results
We evaluated the influence of fluid status on hemoglobin concentrations and the cardiovascular and renal outcomes in a prospective cohort of 326 patients with stage 3 to 5 CKD. Fluid status, as defined by overhydration (OH) level measured with bioimpedance, was negatively correlated with hemoglobin concentrations at baseline (r=−0.438, P<0.001). In multivariate regression analysis, OH remained an independent predictor of hemoglobin, second only to estimated glomerular filtration rate. Patients were stratified into 3 groups: no anemia (n=105), true anemia (n=82), and anemia with excess OH (n=139) (relative OH level ≥7%, the 90th percentile for the healthy population). During a median follow‐up of 2.2 years, there was no difference in cardiovascular and renal risks between patients with true anemia and those with no anemia in the adjusted Cox proportional hazards models. However, patients with anemia with excess OH had a significantly increased risk of cardiovascular morbidity and mortality and CKD progression relative to those with true anemia and those with no anemia, respectively.
Fluid retention is associated with the severity of anemia and adverse cardiovascular and renal outcomes in patients with CKD. Further research is warranted to clarify whether the correction of fluid retention, instead of increasing erythropoiesis, would improve outcomes of CKD‐associated anemia.
PMCID: PMC4330071  PMID: 25559015
anemia; bioimpedance; cardiovascular; kidney; overhydration
2.  Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study 
PLoS Medicine  2013;10(12):e1001575.
Ric Price and colleagues use hospital-based surveillance data to estimate the risk of severe anemia and mortality associated with endemic Plasmodium species in southern Papua, Indonesia.
Please see later in the article for the Editors' Summary
The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia.
Methods and Findings
Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81–9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16–9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44–9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49–9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99–3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00–2.23), 1.87 (95% CI 1.74–2.01), and 2.18 (95% CI 1.76–2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%–13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%–16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17–6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses.
In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.
Please see later in the article for the Editors' Summary
Editors' Summary
Malaria—a mosquito-borne parasitic disease—is a global public health problem. Five parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths—about a million every year. All these parasites enter their human host when an infected mosquito takes a blood meal. The parasites migrate to the liver where they replicate and mature into a parasitic form known as merozoites. After 8–9 days, the merozoites are released from the liver cells and invade red blood cells where they replicate rapidly before bursting out and infecting more red blood cells. Malaria's recurring flu-like symptoms are caused by this cyclical increase in parasites in the blood. Malaria needs to be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia (a reduction in red blood cell numbers) and can damage the brain and other vital organs by blocking the capillaries that supply these organs with blood.
Why Was This Study Done?
It is unclear what proportion of anemia is attributable to non-falciparum malarias in regions of the world where several species of malaria parasite are always present (Plasmodium co-endemicity). Public health officials in such regions need to know whether non-falciparum malarias are a major cause of anemia when designing malaria control strategies. If P. vivax, for example, is a major cause of anemia in an area where P. vivax and P. falciparum co-exist, then any malaria control strategies that are implemented need to take into account the biological differences between the parasites. In this hospital-based cohort study, the researchers investigate the burden of severe anemia from the endemic Plasmodium species in southern Papua, Indonesia.
What Did the Researchers Do and Find?
The researchers used hospital record numbers to link clinical and laboratory data for patients presenting to a referral hospital in southern Papua over an 8-year period. The hemoglobin level (an indicator of anemia) was measured in about a quarter of hospital presentations (some patients attended the hospital several times). A third of the presentations who had their hemoglobin level determined (67,696 presentations) had clinical malaria. Patients with P. malariae infection had the lowest average hemoglobin concentration. Patients with mixed species, P. falciparum, and P. vivax infections had slightly higher average hemoglobin levels but all these levels were below the normal range for people living in Papua. Among the patients who had their hemoglobin status assessed, 3.7% had severe anemia. After allowing for other factors that alter the risk of anemia (“confounding” factors such as age), patients with mixed Plasmodium infection were more than three times as likely to have severe anemia as patients without malaria. Patients with P. falciparum, P. vivax, or P. malariae infections were about twice as likely to have severe anemia as patients without malaria. About 12.2% of severe anemia was attributable to non-falciparum infections, 15.1% was attributable to P. falciparum monoinfections, and P. vivax was the dominant cause of severe anemia in infancy. Finally, compared to patients without anemia, patients with severe anemia had nearly a 6-fold higher risk of death.
What Do These Findings Mean?
These findings provide a comparative assessment of the pattern of anemia associated with non-falciparum malarias in Papua and an estimate of the public health importance of these malarias. Although the accuracy of these findings may be affected by residual confounding (for example, the researchers did not consider nutritional status when calculating how much malaria infection increases the risk of anemia) and other limitations of the study design, non-falciparum malarias clearly make a major contribution to the burden of anemia in southern Papua. In particular, these findings reveal the large contribution that P. vivax makes to severe anemia in infancy, show that the hematological (blood-related) impact of P. malariae is most apparent in adulthood, and suggest, in contrast to some previous reports, that mixed P. vivax/P. falciparum infection is associated with a higher risk of severe anemia than monoinfection with either species. These findings, which need to be confirmed in other settings, highlight the public health importance of implementing integrated malaria control strategies that aim to control all Plasmodium species rather than a single species in regions of Plasmodium co-endemicity.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Gosling and Hsiang
Information is available from the World Health Organization on malaria (in several languages); the 2012 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including information on different Plasmodium species and a selection of personal stories about malaria
The Malaria Vaccine Initiative has fact sheets on Plasmodium falciparum malaria and on Plasmodium vivax malaria
MedlinePlus provides links to additional information on malaria and on anemia (in English and Spanish)
Information is available from the WorldWide Antimalarial Resistance Network on antimalarial drug resistance for P. falciparum and P. vivax
PMCID: PMC3866090  PMID: 24358031
3.  Threshold Haemoglobin Levels and the Prognosis of Stable Coronary Disease: Two New Cohorts and a Systematic Review and Meta-Analysis 
PLoS Medicine  2011;8(5):e1000439.
Anoop Shah and colleagues performed a retrospective cohort study and a systematic review, and show evidence that in people with stable coronary disease there were threshold hemoglobin values below which mortality increased in a graded, continuous fashion.
Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated.
Methods and findings
A retrospective cohort study was carried out using the UK General Practice Research Database. 20,131 people with a new diagnosis of stable angina and no previous acute coronary syndrome, and 14,171 people with first MI who survived for at least 7 days were followed up for a mean of 3.2 years. Using semi-parametric Cox regression and multiple adjustment, there was evidence of threshold haemoglobin values below which mortality increased in a graded continuous fashion. For men with MI, the threshold value was 13.5 g/dl (95% confidence interval [CI] 13.2–13.9); the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 (95% CI 1.76–2.29) compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl; 95% CI 12.1–13.5) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI. We did a systematic review and meta-analysis that identified ten previously published studies, reporting a total of only 1,127 endpoints, but none evaluated thresholds of risk.
There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here. Intervention trials would clarify whether increasing the haemoglobin concentration reduces mortality.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries, accounting for 16.3%, 13.9%, and 9.4% of all deaths, respectively, in 2004. Many risks factors, such as high blood pressure and high blood cholesterol level, are known to be associated with coronary artery disease, and prevention and treatment of such factors remains one of the key strategies in the management of coronary artery disease. Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.
Why was This Study Done?
Much more needs to be understood about the relationship between low hemoglobin and coronary artery disease before hemoglobin levels can potentially be used as a clinical prognostic biomarker. Previous studies have been limited in their ability to describe the shape of this relationship—which means that it is uncertain whether there is a “best” hemoglobin threshold or a continuous graded relationship from “good” to “bad”—to assess gender differences, and to compare patients with angina or who have experienced previous myocardial infarction. In order to inform these knowledge gaps, the researchers conducted a retrospective analysis of patients from a prospective observational cohort as well as a systematic review and meta-analysis (statistical analysis) of previous studies.
What Did the Researchers Do and Find?
The researchers conducted a systematic review and meta-analysis of previous studies and found ten relevant studies, but none evaluated thresholds of risk, only linear relationships.
The researchers carried out a new study using the UK's General Practice Research Database—a national research tool that uses anonymized electronic clinical records of a representative sample of the UK population, with details of consultations, diagnoses, referrals, prescriptions, and test results—as the basis for their analysis. They identified and collected information from two cohorts of patients: those with new onset stable angina and no previous acute coronary syndrome; and those with a first myocardial infarction (heart attack). For these patients, the researchers also looked at all values of routinely recorded blood parameters (including hemoglobin) and information on established cardiovascular risk factors, such as smoking. The researchers followed up patients using death of any cause as a primary endpoint and put this data into a statistical model to identify upper and lower thresholds of an optimal hemoglobin range beyond which mortality risk increased.
The researchers found that there was a threshold hemoglobin value below which mortality continuously increased in a graded manner. For men with myocardial infarction, the threshold value was 13.5 g/dl: 29.5% of patients had hemoglobin below this threshold and had a hazard ratio for mortality of 2.00 compared to those with hemoglobin values in the lowest risk range. Women had a lower threshold hemoglobin value than men: 12.8 g/dl for women with myocardial infarction, but the shape and strength of association did not differ between the genders, or between patients with angina and myocardial infarction.
What Do These Findings Mean?
These findings suggest that there are thresholds of hemoglobin that are associated with increased risk of mortality in patients with angina or myocardial infarction. A substantial proportion of patients (15%–30%) have a hemoglobin level that places them at markedly higher risk of death compared to patients with lowest risk hemoglobin levels and importantly, these thresholds are higher than clinicians might anticipate—and are remarkably similar to World Health Organization anemia thresholds of 12 g/dl for women and 13 g/dl for men. Despite the limitations of these observational findings, this study supports the rationale for conducting future randomized controlled trials to assess whether hemoglobin levels are causal and whether clinicians should intervene to increase hemoglobin levels, for example by oral iron supplementation.
Additional Information
Please access these Web sites via the online version of this summary at
Wikipedia provides information about hemoglobin (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization provides an overview of the global prevalence of coronary artery disease, a factsheet on the top ten causes of death, as well as information on anemia
PMCID: PMC3104976  PMID: 21655315
4.  The effects of iron deficiency anemia on p wave duration and dispersion 
Clinics  2010;65(11):1067-1071.
The association between P wave dispersion and iron deficiency anemia has not been documented in the literature. In this study, we evaluated P wave dispersion in patients with iron deficiency anemia and the possible relationships between P wave dispersion and other echocardiographic parameters.
The iron status of an individual may play an important role in cardiovascular health. Anemia is an independent risk factor for adverse cardiovascular outcomes. P wave dispersion is a simple electrocardiographic marker that has a predictive value for the development of atrial fibrillation. Apart from cardiovascular diseases, several conditions, such as seasonal variation, alcohol intake and caffeine ingestion, have been demonstrated to affect P wave dispersion.
The study included 97 patients who had iron deficiency anemia and 50 healthy subjects. The cases were evaluated with a clinical examination and diagnostic tests that included 12‐lead electrocardiography and transthoracic echocardiography.
Compared to the control group, patients with iron deficiency anemia showed significantly longer maximum P wave duration (Pmax) (91.1±18.0 vs. 85.8±6.7 msec, p = 0.054), P wave dispersion (PWD) (48.1±7.7 vs. 40.9±5.6 msec, p<0.001), mitral inflow deceleration time (DT) (197.5±27.9 vs. 178.8±8.9 msec, p<0.001) and isovolumetric relaxation time (IVRT) (93.3±9.2 vs. 77.4±8.2 msec, p<0.001); they also showed increased heart rate (85.7±16.1 vs. 69.0±4.4, p<0.001) and frequency of diastolic dysfunction (7 (7.2%) vs. 0). Correlation analysis revealed that PWD was significantly correlated with IVRT, DT, heart rate, the presence of anemia and hemoglobin level.
Iron deficiency anemia may be associated with prolonged P wave duration and dispersion and impaired diastolic left ventricular filling.
PMCID: PMC2999696  PMID: 21243273
Diastolic dysfunction; Electrocardiogram; Iron deficiency; Anemia; P wave; Dispersion
5.  Dose of Erythropoiesis-Stimulating Agents and Adverse Outcomes in CKD: A Metaregression Analysis 
Targeting higher hemoglobin with erythropoiesis-stimulating agents (ESAs) to treat anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.
Study Design
Meta-regression analysis examining the association of ESA dose with adverse outcomes, independent of target or achieved hemoglobin.
Setting and Population
Patients with anemia of CKD, irrespective of dialysis status.
Selection Criteria for Studies
We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for treatment of anemia in adults with CKD, with minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.
ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.
All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression or transfusion requirement.
31 trials (12,956 patients) met criteria. All-cause mortality was associated with higher (per epoetin-alfa–equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10–1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02–1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin (IRR, 1.48; 95% CI, 1.02- 2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin (IRR, 2 1.41; 95% CI, 1.08–1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction but not statistically significant. Higher total-study-period mean ESA dose was also associated with increased rate of hypertension, stroke, and thrombotic events including dialysis vascular access-related thrombotic events.
use of study-level aggregated data; use of epoetin alfa–equivalent doses; lack of adjustment for confounders.
In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin.
PMCID: PMC3525813  PMID: 22921639
erythropoietin; ESA; epoetin; darbepoetin; anemia; CKD; dose; mortality; cardiovascular morbidity; meta-regression
6.  Anemia and Associated Clinical Outcomes in Patients with Heart Failure Due to Reduced Left Ventricular Systolic Function 
Clinical cardiology  2013;36(10):611-620.
Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF.
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in 2331 patients with HFREF. Patients with New York Heart Association class 2–4 HF and left ventricular ejection fractions of ≤ 35% were recruited. Hemoglobin (Hb) was measured up to one year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb < 13 g/dl and <12 g/dl in men and women, respectively. Hb was assessed in two models; a global prediction model that had been previously developed and a modified model including variables associated with anemia and the studied outcomes.
Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female gender, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without, p<0.001. The secondary outcomes of all-cause mortality alone, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization occurred in 23 % vs 15%, 67% vs 54%, and 44 vs 29%, respectively, p<0.001. Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively, p<0.001. For the global model, there was an association observed for anemia and all-cause mortality or hospitalization, adjusted hazard ratio (HR)=1.15, 95% CI 1.01–1.32, p=0.04, but other outcomes were not significant at p<0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25, 95% CI 1.10–1.42, p<0.001. There were independent associations between anemia and all-cause death, HR=1.11, 95% CI 0.87–1.42, p=0.38; cardiovascular death or cardiovascular hospitalization, HR=1.16, 95% CI 1.01–1.33, p=0.035; and cardiovascular death and heart failure hospitalization, HR=1.27, 95% CI 1.06–1.51, p=0.008.
Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of cardiovascular death and cardiovascular/heart failure hospitalizations as composite endpoints.
PMCID: PMC4008125  PMID: 23929781
heart failure; chronic kidney disease; anemia; glomerular filtration rate; renal insufficiency; hospitalization; mortality
7.  Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery 
Anemia is an established adverse risk factor in cardiovascular disease. However, the effect of preoperative anemia is not well defined in heart surgery. This study evaluates the effect of preoperative anemia on early clinical outcomes in patients undergoing cardiac surgery.
A retrospective, observational, cohort study of prospectively collected data was undertaken on 7,738 consecutive patients undergoing heart surgery between April 2003 and February 2009. Of these, 1,856 patients with preoperative anemia were compared to 5,882 patients without anemia (control group). According to the World Health Organization, anemia was defined as hemoglobin level < 13 g/dl for men and <12 g/dl for women. Selection bias not controlled by multivariable methods was assessed with propensity-adjustment method.
Overall mortality was 2.1%. Preoperative anemia was associated with tripling in the risk of death (4.6% vs 1.5%, p < 0.0001) and postoperative renal dysfunction (18.5% vs 6.5%, p < 0.0001). There was also a significant difference between the anemic and non-anemic group in the risk of postoperative stroke (1.9% vs 1.1%, p = 0.008), atrial fibrillation (36.7% vs 33%, p = 0.003) and length of hospital stay > 7 days (54% vs 36.7%, p < 0.0001). In propensity-adjusted, multivariable logistic regression, preoperative anemia was an independent predictor of mortality (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02 to 2.03), postoperative renal dysfunction (OR 1.73, 95% CI 1.43 to 2.1) and length of hospital stay > 7 days (OR 1.3, 95% CI 1.15 to 1.47).
In patients undergoing heart surgery, preoperative anemia is associated with an increased risk of mortality and postoperative morbidity.
PMCID: PMC4237817  PMID: 25096231
Anemia; Cardiac surgery; Outcome
8.  Anemia and the onset of gout in a population-based cohort of adults: Atherosclerosis Risk in Communities study 
Arthritis Research & Therapy  2012;14(4):R193.
There is a growing prevalence of gout in the US and worldwide. Gout is a recognized risk factor for cardiovascular disease (CVD). It is unclear whether other risk factors for CVD are also associated with increased risk of gout. Anemia is one such CVD risk factor. No studies have evaluated the relationship between anemia and gout. We tested whether anemia was associated with incident gout independent of comorbid conditions in Atherosclerosis Risk in the Communities.
This population-based cohort recruited 15,792 individuals in 1987 to 1989 from four US communities and contained nine years of follow-up. Anemia was defined as hemoglobin <13.5 g/dL for men and <12 g/dL for women. Using a Cox Proportional Hazards model, we estimated the hazard ratio (HR) and confidence intervals (CI) of incident gout by baseline anemia, adjusted for confounders (sex, race, estimated glomerular filtration rate, body mass index and alcohol intake) and clinical factors (coronary heart disease, congestive heart failure, diabetes, hypertension, diuretic use and serum urate level).
Among the 10,791 participants, 10% had anemia at baseline. There were 271 cases of incident gout. Patients with anemia had a two-fold increased risk of developing gout over nine years (HR = 2.01, 95% CI: 1.46, 2.76). Anemia was associated with incident gout independent of known gout risk factors, confounders and clinical risk factors (HR = 1.73, 95% CI: 1.24, 2.41). This association persisted after additionally adjusting for serum urate level (HR = 1.83, 95% CI: 1.30, 2.57).
We identified anemia as a novel risk factor for gout. Anemia was associated with an approximately two-fold increased risk of gout-independent kidney function and serum urate. These findings suggest that anemia is a risk factor for gout on par with other chronic conditions such as obesity and diabetes. The biological mechanism linking anemia to gout remains unclear.
PMCID: PMC3580590  PMID: 22906142
9.  Clinical Profile and Prognostic Value of Anemia at the Time of Admission and Discharge Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction 
Circulation. Heart failure  2014;7(3):401-408.
Anemia has been associated with worse outcomes in patients with chronic heart failure (HF). We aimed to characterize the clinical profile and postdischarge outcomes of hospitalized HF patients with anemia at admission or discharge.
Methods and Results
An analysis was performed on 3731 (90%) of 4133 hospitalized HF patients with ejection fraction ≤40% enrolled in the Efficacy of Vasopressin Antagonist in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial with baseline hemoglobin data, comparing the clinical characteristics and outcomes (all-cause mortality and cardiovascular mortality or HF hospitalization) of patients with and without anemia (hemoglobin <12 g/dL for women and <13 g/dL for men) on admission or discharge/day 7. Overall, 1277 patients (34%) were anemic at baseline, which persisted through discharge in 73% and resolved in 27%; 6% of patients without baseline anemia developed anemia by discharge or day 7. Patients with anemia were older, with lower blood pressure, and higher creatinine and natriuretic peptide levels compared with those without anemia (all P<0.05). After risk adjustment, anemia at discharge, but not admission, was independently associated with increased all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.05–1.60; P=0.015; and hazard ratio, 0.94; 95% confidence interval, 0.76–1.15; P=0.53, respectively) and cardiovascular mortality plus HF hospitalization early postdischarge (≤100 days; hazard ratio 1.73; 95% confidence interval, 1.37–2.18; P<0.001; and hazard ratio, 0.92; 95% confidence interval, 0.73–1.16; P=0.47, respectively). Neither baseline nor discharge anemia was associated with long-term cardiovascular mortality plus HF hospitalization (>100 days) on adjusted analysis (both P>0.1).
Among hospitalized HF patients with reduced ejection fraction, modest anemia at discharge but not baseline was associated with increased all-cause mortality and short-term cardiovascular mortality plus HF hospitalization.
Clinical Trial Registration
URL: Unique identifier: NCT00071331.
PMCID: PMC4151504  PMID: 24737459
anemia; heart failure; hemoglobin; hospitalization
10.  Diminished Quality of Life and Physical Function in Community-Dwelling Elderly with Anemia 
Medicine  2009;88(2):107-114.
The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity and mortality. It is not clear to what extent these outcomes are the result of the anemia or concurrent illness. We performed a cross-sectional, observational study to determine whether lower hemoglobin concentrations in older adults are associated with reduced health-related quality of life, functional status, depression, disability, and physical strength, independent of chronic disease. Three sites participated in this research; an academic geriatric practice, a hospital based geriatric out patient unit, and a community-based multi-specialty internal medicine group. Health-related quality of life and functional status were measured using the Short Form-36 Health Survey (SF-36) and the Functional Assessment of Chronic Illness Therapy-Anemia (FACIT-An). Disability and depression were assessed using the Instrumental Activities of Daily Living (IADL) and the Geriatric Depression Scale (GDS) questionnaires, respectively. Handgrip strength was used as a physical performance measure. Anemia was defined as hemoglobin < 13 g/dL for men or < 12 g/dL for women. The mean SF-36 physical health component summary scores were 38.9 (with anemia) and 44.1 (without anemia), (P < 0.001). Anemia was associated with greater fatigue (P < 0.001), lower handgrip strength (P = 0.014), increased number of disabilities (P = 0.005) and more depressive symptoms (P = 0.002). Multivariate regression analysis, adjusted for demographic and clinical characteristics, demonstrated strong associations for reduced hemoglobin, even within the “normal” range, and poorer health-related quality of life across multiple domains. Thus, anemia was independently associated with clinically significant impairments in multiple domains of health-related quality of life, especially in measures of functional limitation. Mildly low hemoglobin levels, even when above the WHO anemia threshold, were associated with significant declines in quality of life among the elderly.
PMCID: PMC2893336  PMID: 19282701
11.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
12.  Anemia on Admission Is an Independent Predictor of Long-Term Mortality in Hip Fracture Population 
Medicine  2016;95(5):e2469.
Anemia is a disputable factor for long-term mortality in hip fracture population in previous studies. Previous studies indicated that the level of hemoglobin (Hb) might fluctuate due to various factors, such as comorbidities and in-hospital interventions, and the changing level of Hb, may lead to discordance diagnosis of anemia and thus to the conflicting conclusions on prognostic value of anemia. So in this study, we aim to compare factors affecting the diagnosis of anemia at different time-points, admission, postoperation, and discharge, and to determine which the time point is most suitable for mortality prediction.
This prospective cohort study included 1330 hip fracture patients from 1 January 2000 to 18 November 2012. Hb levels at 3 different time points, such as admission, postoperation, and discharge, were collected and used to stratify the cohort into anemia and nonanemia groups. Candidate factors including commodities, perioperative factors, blood transfusion, and other in-hospital interventions were collected before discharge. Logistic regression analyses were performed to detect risk factors for anemia for the 3 time points separately. Kaplan–Meier and multivariate Cox regression analyses were used to evaluate the association between anemia and 2-year mortality.
Factors affecting the diagnosis of anemia were different for the 3 time points. Age, female sex, American Society of Anesthesiologists score (ASA), and intertrochanteric fracture were associated with admission anemia, while surgical procedure, surgical duration, blood transfusion, blood loss during the operation, and drainage volume were major risk factors for postoperation anemia. Cox proportional-hazards regression analysis suggested that the risk of all-cause mortality was higher in the anemia group on admission (1.680, 95%CI: 1.201–2.350, P < 0.01), but not postoperation or on discharge, after adjustment for confounding factors.
Our study showed that risk factors for anemia varied at different time points, and therapy interventions would greatly affect the status of postoperation and discharge anemia in hip fracture patients. The take-home message is when anemia is used for mortality prediction in these patients, a specific time point should be chosen. We suggest that only admission anemia should be used for mortality prediction, but not postoperation nor discharge anemia.
PMCID: PMC4748873  PMID: 26844456
13.  Prevalence, severity, and related factors of anemia in HIV/AIDS patients 
The prevalence of anemia in HIV infected patients has not been well characterized in Iran. This study aimed to describe the prevalence of anemia and related factors in HIV positive patients.
Materials and Methods:
In a cross-sectional study, anemia prevalence and risk factors of 212 HIV positive patients were assessed, at the behavioral disease consulting center in Isfahan. The relationship between anemia, demographic variables, and clinical histories were analyzed. Mild to moderate anemia was defined as hemoglobin 8–13 g/dL for men and 8–12 g/dL for women. Severe anemia was defined as hemoglobin, 8 g/dL.
A total of 212 HIV positive patients with a mean±SD age of 36.1 ± 9.1 years were assessed. We found that hemoglobin levels were between 4.7 and 16.5 gr/dL. In this study, the overall prevalence of anemia was 71%, with the majority of patients having mild to moderate anemia. Mild to moderate anemia and severe anemia occurred in 67% and 4% of patients, respectively. The mean absolute CD4 count was 348 ± 267.8 cells/cubic mm. Sixty one of 212 patients were at late stage of HIV infection (males=51 and female=10). Of the 212 HIV positive patients enrolled, 17 (8%) had a positive history of tuberculosis. We found a strong association between anemia and death.
Normocytic anemia with decreased reticulocyte count was the most common type of anemia in overall. Prevalence of anemia in this study is relatively higher than other similar studies. Such a high prevalence of anemia needs close monitoring of patients on a zidovudine-based regimen. Better screening for anemia and infectious diseases, and modified harm reduction strategy (HRS) for injection drug users are primary needs in HIV seropositive patients.
PMCID: PMC3525030  PMID: 23264786
AIDS; anemia; HIV positive
14.  Preoperative Anemia in Total Joint Arthroplasty: Is It Associated with Periprosthetic Joint Infection? 
Anemia is common in patients undergoing total joint arthroplasty (TJA). Numerous studies have associated anemia with increased risk of infection, length of hospital stay, and mortality in surgical populations. However, it is unclear whether and to what degree preoperative anemia in patients undergoing TJA influences postoperative periprosthetic joint infection (PJI) and mortality.
We therefore (1) determined the incidence of preoperative anemia in patients undergoing TJA; (2) assessed the possible association between preoperative anemia and subsequent PJI; and (3) explored the relationship between preoperative anemia with postoperative mortality.
We identified 15,722 patients who underwent TJA from January 2000 to June 2007. Anemia was defined as hemoglobin < 12 g/dL in women and hemoglobin < 13 g/dL in men. We determined the effect of preoperative anemia, demographics, and comorbidities on postoperative complications.
Of the 15,222 patients, 19.6% presented with preoperative anemia. PJI occurred more frequently in anemic patients at an incidence of 4.3% in anemic patients compared with 2% in nonanemic patients. Thirty-day (0.4%), 90-day (0.6%), and 1-year (1.8%) mortality rates were not higher in patients with preoperative anemia. Forty-four percent of anemic patients received an allogenic transfusion compared with only 13.4% of nonanemic patients. Anemic patients had increased hospital stays averaging 4.3 days compared with 3.9 days in nonanemic patients. Anemia did not predict cardiac complications.
Our data demonstrate that preoperative anemia is associated with development of subsequent PJI. Preoperative anemia was not associated with 30-day, 60-day, or 1-year mortality in this cohort.
Level of Evidence
Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3442010  PMID: 22773393
15.  Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study 
PLoS Medicine  2013;10(1):e1001372.
In a prospective Australian population-based study linking questionnaire data from 2006–2009 with hospitalisation and death data to June 2010 for 95,038 men aged ≥45 years, Banks and colleagues found that more severe erectile dysfunction was associated with higher risk of cardiovascular disease.
Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes.
Methods and Findings
We conducted a prospective population-based Australian study (the 45 and Up Study) linking questionnaire data from 2006–2009 with hospitalisation and death data to 30 June and 31 Dec 2010 respectively for 95,038 men aged ≥45 y. Cox proportional hazards models were used to examine the relationship of reported severity of erectile dysfunction to all-cause mortality and first CVD-related hospitalisation since baseline in men with and without previous CVD, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and hypertension and/or hypercholesterolaemia treatment. There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60, 95% CI 1.31–1.95), heart failure (8.00, 2.64–24.2), peripheral vascular disease (1.92, 1.12–3.29), “other” CVD (1.26, 1.05–1.51), all CVD combined (1.35, 1.19–1.53), and all-cause mortality (1.93, 1.52–2.44). For men with previous CVD, corresponding RRs (95% CI) were 1.70 (1.46–1.98), 4.40 (2.64–7.33), 2.46 (1.63–3.70), 1.40 (1.21–1.63), 1.64 (1.48–1.81), and 2.37 (1.87–3.01), respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66, 1.22–2.26), atrioventricular and left bundle branch block (6.62, 1.86–23.56), and (peripheral) atherosclerosis (2.47, 1.18–5.15), with no significant difference in risk for conditions such as primary hypertension (0.61, 0.16–2.35) and intracerebral haemorrhage (0.78, 0.20–2.97).
These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment. The utility of erectile dysfunction as a clinical risk prediction tool requires specific testing.
Please see later in the article for the Editors' Summary
Editors' Summary
Erectile dysfunction is the medical term used when a man is unable to achieve or sustain an erection of his penis suitable for sexual intercourse. Although a sensitive topic that can cause much embarrassment and distress, erectile dysfunction is very common, with an estimated 40% of men over the age of 40 years experiencing frequent or occasional difficulties. The most common causes of erectile dysfunction are medications, chronic illnesses such as diabetes, and drinking too much alcohol. Stress and mental health problems can also cause or worsen erectile dysfunction. There is also increasing evidence that erectile dysfunction may actually be a symptom of cardiovascular disease—a leading cause of death worldwide—as erectile dysfunction could indicate a problem with blood vessels or poor blood flow commonly associated with cardiovascular disease.
Why Was This Study Done?
Although previous studies have suggested that erectile dysfunction can serve as a marker for cardiovascular disease in men not previously diagnosed with the condition, few studies to date have investigated whether erectile dysfunction could also indicate worsening disease in men already diagnosed with cardiovascular disease. In addition, previous studies have typically been small and have not graded the severity of erectile dysfunction or investigated the specific types of cardiovascular disease associated with erectile dysfunction. In this large study conducted in Australia, the researchers investigated the relationship of the severity of erectile dysfunction with a range of cardiovascular disease outcomes among men with and without a previous diagnosis of cardiovascular disease.
What Did the Researchers Do and Find?
The researchers used information from the established 45 and Up Study, a large cohort study that includes 123,775 men aged 45 and over, selected at random from the general population of New South Wales, a large region of Australia. A total of 95,038 men were included in this analysis. The male participants completed a postal questionnaire that included a question on erectile functioning, which allowed the researchers to define erectile dysfunction as none, mild, moderate, or severe. Using information captured in the New South Wales Admitted Patient Data Collection—a complete record of all public and private hospital admissions, including the reasons for admission and the clinical diagnosis—and the government death register, the researchers were able to determine health outcomes of all study participants. They then used a statistical model to estimate hospital admissions for cardiovascular disease events for different levels of erectile dysfunction.
The researchers found that the rates of severe erectile dysfunction among study participants were 2.2% for men aged 45–54 years, 6.8% for men aged 55–64 years, 20.2% for men aged 65–74 years, 50.0% for men aged 75–84 years, and 75.4% for men aged 85 years and over. During the study period, the researchers recorded 7,855 hospital admissions related to cardiovascular disease and 2,304 deaths. The researchers found that among men without previous cardiovascular disease, those with severe erectile dysfunction were more likely to develop ischemic heart disease (risk 1.60), heart failure (risk 8.00), peripheral vascular disease (risk 1.92), and other causes of cardiovascular disease (risk 1.26) than men without erectile dysfunction. The risks of heart attacks and heart conduction problems were also increased (1.66 and 6.62, respectively). Furthermore, the combined risk of all cardiovascular disease outcomes was 1.35, and the overall risk of death was also higher (risk 1.93) in these men. The researchers found that these increased risks were similar in men with erectile dysfunction who had previously been diagnosed with cardiovascular disease.
What Do These Findings Mean?
These findings suggest that compared to men without erectile dysfunction, there is an increasing risk of ischemic heart disease, peripheral vascular disease, and death from all causes in those with increasing degrees of severity of erectile dysfunction. The authors emphasize that erectile dysfunction is a risk marker for cardiovascular disease, not a risk factor that causes cardiovascular disease. These findings add to previous studies and highlight the need to consider erectile dysfunction in relation to the risk of different types of cardiovascular disease, including heart failure and heart conduction disorders. However, the study's reliance on the answer to a single self-assessed question on erectile functioning limits the findings. Nevertheless, these findings provide useful information for clinicians: men with erectile dysfunction are at higher risk of cardiovascular disease, and the worse the erectile dysfunction, the higher the risk of cardiovascular disease. Men with erectile dysfunction, even at mild or moderate levels, should be screened and treated for cardiovascular disease accordingly.
Additional Information
Please access these websites via the online version of this summary at
Wikipedia defines erectile dysfunction (note that Wikipedia is a free online encyclopedia that anyone can edit)
MedlinePlus also has some useful patient information on erectile dysfunction
The Mayo Clinic has patient-friendly information on the causes of, and treatments for, erectile dysfunction, and also includes information on the link with cardiovascular disease
The National Heart Foundation of Australia provides information for health professionals, patients, and the general public about how to prevent and manage cardiovascular disease, including assessment and management of cardiovascular disease risk
PMCID: PMC3558249  PMID: 23382654
16.  Anemia and blood transfusion in a surgical intensive care unit 
Critical Care  2010;14(3):R92.
Studies in intensive care unit (ICU) patients have suggested that anemia and blood transfusions can influence outcomes, but these effects have not been widely investigated specifically in surgical ICU patients.
We retrospectively analyzed the prospectively collected data from all adult patients (>18 years old) admitted to a 50-bed surgical ICU between 1st March 2004 and 30th July 2006.
Of the 5925 patients admitted during the study period, 1833 (30.9%) received a blood transfusion in the ICU. Hemoglobin concentrations were < 9 g/dl on at least one occasion in 57.6% of patients. Lower hemoglobin concentrations were associated with a higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, greater mortality rates, and longer ICU and hospital lengths of stay. Transfused patients had higher ICU (12.5 vs. 3.2%) and hospital (18.3 vs. 6.5%) mortality rates (both p < 0.001) than non-transfused patients. However, ICU and in-hospital mortality rates were similar among transfused and non-transfused matched pairs according to a propensity score (n = 1184 pairs), and after adjustment for possible confounders in a multivariable analysis, higher hemoglobin concentrations (RR 0.97[0.95-0.98], per 1 g/dl, p < 0.001) and blood transfusions (RR 0.96[0.92-0.99], p = 0.031) were independently associated with a lower risk of in-hospital death, especially in patients aged from 66 to 80 years, in patients admitted to the ICU after non-cardiovascular surgery, in patients with higher severity scores, and in patients with severe sepsis.
In this group of surgical ICU patients, anemia was common and was associated with higher morbidity and mortality. Higher hemoglobin concentrations and receipt of a blood transfusion were independently associated with a lower risk of in-hospital death. Randomized control studies are warranted to confirm the potential benefit of blood transfusions in these subpopulations.
PMCID: PMC2911729  PMID: 20497535
17.  Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants 
JAMA  2016;315(9):889-897.
Data regarding the contribution of red blood cell (RBC) transfusion and anemia to necrotizing enterocolitis (NEC) are conflicting. These associations have not been prospectively evaluated, accounting for repeated, time-varying exposures.
To determine the relationship between RBC transfusion, severe anemia, and NEC.
Design, Setting, and Participants
In a secondary, prospective, multicenter observational cohort study from January 2010 to February 2014, very low-birth-weight (VLBW, ≤1500 g) infants, within 5 days of birth, were enrolled at 3 level III neonatal intensive care units in Atlanta, Georgia. Two hospitals were academically affiliated and 1 was a community hospital. Infants received follow-up until 90 days, hospital discharge, transfer to a non–study-affiliated hospital, or death (whichever came first). Multivariable competing-risks Cox regression was used, including adjustment for birth weight, center, breastfeeding, illness severity, and duration of initial antibiotic treatment, to evaluate the association between RBC transfusion, severe anemia, and NEC.
The primary exposure was RBC transfusion. The secondary exposure was severe anemia, defined a priori as a hemoglobin level of 8 g/dL or less. Both exposures were evaluated as time-varying covariates at weekly intervals.
Main Outcomes and Measures
Necrotizing enterocolitis, defined as Bell stage 2 or greater by preplanned adjudication. Mortality was evaluated as a competing risk.
Of 600 VLBW infants enrolled, 598 were evaluated. Forty-four (7.4%) infants developed NEC. Thirty-two (5.4%) infants died (all cause). Fifty-three percent of infants (319) received a total of 1430 RBC transfusion exposures. The unadjusted cumulative incidence of NEC at week 8 among RBC transfusion-exposed infants was 9.9% (95% CI, 6.9%-14.2%) vs 4.6% (95% CI, 2.6%-8.0%) among those who were unexposed. In multivariable analysis, RBC transfusion in a given week was not significantly related to the rate of NEC (adjusted cause-specific hazard ratio, 0.44 [95% CI, 0.17-1.12]; P = .09). Based on evaluation of 4565 longitudinal measurements of hemoglobin (median, 7 per infant), the rate of NEC was significantly increased among VLBW infants with severe anemia in a given week compared with those who did not have severe anemia (adjusted cause-specific hazard ratio, 5.99 [95% CI, 2.00-18.0]; P = .001).
Conclusions and Relevance
Among VLBW infants, severe anemia, but not RBC transfusion, was associated with an increased risk of NEC. Further studies are needed to evaluate whether preventing severe anemia is more important than minimizing RBC transfusion.
PMCID: PMC4805423  PMID: 26934258
18.  Erythropoietin Levels in Elderly Patients with Anemia of Unknown Etiology 
PLoS ONE  2016;11(6):e0157279.
In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of “anemia of unknown etiology” and whether this trend persists after accounting for confounders.
This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient’s anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS), suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR) and Charlson Comorbidity Index.
A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities.
We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology.
PMCID: PMC4911007  PMID: 27310832
19.  Anemia, Blood Transfusion Requirements and Mortality Risk in Human Immunodeficiency Virus-Infected Adults Requiring Acute Medical Admission to Hospital in South Africa 
Open Forum Infectious Diseases  2015;2(4):ofv173.
Background. Morbidity and mortality remain high among hospitalized patients infected with human immunodeficiency virus (HIV) in sub-Saharan Africa despite widespread availability of antiretroviral therapy. Severe anemia is likely one important driver, and some evidence suggests that blood transfusions may accelerate HIV progression and paradoxically increase short-term mortality. We investigated the relationship between anemia, blood transfusions, and mortality in a South African district hospital.
Methods. Unselected consecutive HIV-infected adults requiring acute medical admission to a Cape Town township district hospital were recruited. Admission hemoglobin concentrations were used to classify anemia severity according to World Health Organization/AIDS Clinical Trials Group criteria. Vital status was determined at 90 days, and Cox regression analyses were used to determine independent predictors of mortality.
Results. Of 585 HIV-infected patients enrolled, 578 (98.8%) were included in the analysis. Anemia was detected in 84.8% of patients and was severe (hemoglobin, 6.5–7.9 g/dL) or life-threatening (hemoglobin, <6.5 g/dL) in 17.3% and 13.3%, respectively. Within 90 days of the date of admission, 13.5% (n = 78) patients received at least 1 blood transfusion with red cell concentrate and 77 (13.3%) patients died. In univariable analysis, baseline hemoglobin and receipt of blood transfusion were associated with increased mortality risk. However, in multivariable analysis, neither hemoglobin nor receipt of a blood transfusion were independently associated with greater mortality risk. Acquired immune deficiency syndrome-defining illnesses other than tuberculosis and impaired renal function independently predicted mortality.
Conclusions. Newly admitted HIV-infected adults had a high prevalence of severe or life-threatening anemia and blood transfusions were frequently required. However, after adjustment for confounders, blood transfusions did not confer an increased mortality risk.
PMCID: PMC4693115  PMID: 26730391
Africa; AIDS; anemia; blood transfusion; HIV; hospitalized; mortality
20.  How low is too low? Cardiac risks with anemia 
Critical Care  2004;8(Suppl 2):S11-S14.
Despite the increasing availability of data supporting more restrictive transfusion practices, the risks and benefits of transfusing critically ill patients continue to evoke controversy. Past retrospective and observational studies suggested that liberal transfusion strategies were more beneficial in patients whose hematocrit levels fell below 30%. An expanding body of literature suggests that an arbitrary trigger for transfusion (the '10/30 rule') is ill advised. A recent randomized controlled trial provided compelling evidence that similar, and in some cases better, outcomes result if a restrictive transfusion strategy is maintained. The impact of this accumulating evidence on clinical practice is evident in large reports, which show that the average transfusion trigger in critically ill patients was a hemoglobin level in the range 8–8.5 g/dl. Based on the available evidence, transfusion in the critically ill patient without active ischemic heart disease should generally be withheld until the hemoglobin level falls to 7 g/dl. Transfusions should be administered as clinically indicated for patients with acute, ongoing blood loss and those who have objective signs and symptoms of anemia despite maintenance of euvolemia. The hemoglobin level at which serious morbidity or mortality occurs in critically ill patients with active ischemic heart disease is a subject of continued debate but it is likely that a set transfusion trigger will not provide an optimal risk–benefit profile in this population.
PMCID: PMC3226154  PMID: 15196315
anemia; blood; cardiac disease; critically ill patients; hemoglobin; transfusion trigger
21.  Mapping the Risk of Anaemia in Preschool-Age Children: The Contribution of Malnutrition, Malaria, and Helminth Infections in West Africa 
PLoS Medicine  2011;8(6):e1000438.
Ricardo Soares Magalhães and colleagues used national cross-sectional household-based demographic health surveys to map the distribution of anemia risk in preschool children in Burkina Faso, Ghana, and Mali.
Childhood anaemia is considered a severe public health problem in most countries of sub-Saharan Africa. We investigated the geographical distribution of prevalence of anaemia and mean haemoglobin concentration (Hb) in children aged 1–4 y (preschool children) in West Africa. The aim was to estimate the geographical risk profile of anaemia accounting for malnutrition, malaria, and helminth infections, the risk of anaemia attributable to these factors, and the number of anaemia cases in preschool children for 2011.
Methods and Findings
National cross-sectional household-based demographic health surveys were conducted in 7,147 children aged 1–4 y in Burkina Faso, Ghana, and Mali in 2003–2006. Bayesian geostatistical models were developed to predict the geographical distribution of mean Hb and anaemia risk, adjusting for the nutritional status of preschool children, the location of their residence, predicted Plasmodium falciparum parasite rate in the 2- to 10-y age group (Pf PR2–10), and predicted prevalence of Schistosoma haematobium and hookworm infections. In the four countries, prevalence of mild, moderate, and severe anaemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The mean Hb was lowest in Burkina Faso (89 g/l), in males (93 g/l), and for children 1–2 y (88 g/l). In West Africa, severe malnutrition, Pf PR2–10, and biological synergisms between S. haematobium and hookworm infections were significantly associated with anaemia risk; an estimated 36.8%, 14.9%, 3.7%, 4.2%, and 0.9% of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium infections, hookworm infections, and S. haematobium/hookworm coinfections, respectively. A large spatial cluster of low mean Hb (<80 g/l) and maximal risk of anaemia (>95%) was predicted for an area shared by Burkina Faso and Mali. We estimate that in 2011, approximately 6.7 million children aged 1–4 y are anaemic in the three study countries.
By mapping the distribution of anaemia risk in preschool children adjusted for malnutrition and parasitic infections, we provide a means to identify the geographical limits of anaemia burden and the contribution that malnutrition and parasites make to anaemia. Spatial targeting of ancillary micronutrient supplementation and control of other anaemia causes, such as malaria and helminth infection, can contribute to efficiently reducing the burden of anaemia in preschool children in Africa.
Please see later in the article for the Editors' Summary
Editors' Summary
Global estimates for the time period 1993–2005 suggest that that worldwide, nearly 300 million children had anemia, that is, hemoglobin levels less than 110 g/l. In sub-Saharan Africa, two-thirds of all children were anemic, representing 83.5 million children. These statistics are important because anemia in infancy and childhood is associated with poor cognitive development, reduced growth, problems with immune function—and ultimately, decreased survival. Malnutrition (including micronutrient deficiency, especially of iron, vitamin A, vitamin C, and folate), undernutrition, and infectious diseases, particularly HIV, malaria, and helminth infections (caused by hookworm and Schistosoma haematobium—which causes urinary schistosomiasis), are major causes of anemia in children. Although iron supplementation can often correct anemia, in some circumstances, iron deficiency can protect against common infectious agents, and giving iron can, on occasion, increase the severity of infectious disease in some children. Focusing on the treatment and prevention of infectious diseases that cause anemia is therefore an important alternative strategy in the treatment of anemia.
Why Was This Study Done?
Control tools for targeting interventions for malaria and helminth infection in sub-Saharan Africa include modern spatial risk prediction methods that combine statistical models with geographical information systems (similar to those used in car navigation systems). However, to date no studies have used these tools to spatially predict the risk of anemia. Furthermore, the contribution that malnutrition and infections make to the overall anemia burden in Africa is largely unknown. In this study the researchers used these tools to predict the prevalence of anemia in three West African countries and to estimate the attributable risk of anemia due to malnutrition, malaria, and helminth infections.
What Did the Researchers Do and Find?
The researchers used geographically linked data from the most recent Demographic and Health Surveys (DHS) in Burkina Faso (2003), Ghana (2003), and Mali (2006), which included capillary blood sampling and testing and detailed anthropometric (height and weight) measurements. A total of 7,147 children aged 1–4 years (3,477 girls and 3,670 boys) in the three countries were included in the analysis. The researchers mapped DHS survey locations in the three study countries using DHS cluster coordinates in a geographic information system. Using data from the Malaria Atlas Project, the researchers extracted spatially predicted values of Plasmodium falciparum parasite rate for each DHS cluster using a geographical information system and used previously reported parasitological survey data of hookworm and S. haematobium infections to predict helminth infection risk across the region. Then the researchers developed spatial prediction models using Bayesian statistics to estimate of the population attributable fraction for specific predictors for anemia. Data from the DHS showed that the prevalence of mild, moderate, and severe anemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The prevalence of stunting, wasting, and being underweight in the study area was 87.8%, 89.7%, and 71.2%, respectively, and the mean P. falciparum parasite rate, and rates of S. haematobium infection, hookworm infection, and S. haematobium/hookworm coinfection for the study area were 52.0%, 26.8%, 8.2%, and 3.6%, respectively. The overall results indicate that in the three countries, approximately 6.7 million children aged 1–4 years have anemia. Severe malnutrition, P. falciparum infection, hookworm infection, S. haematobium infection, and hookworm/S. haematobium coinfection were responsible for an estimated 2.5 million, 1.0 million, 250,000, 285,000, and 61,000 anemia cases, respectively. Central Burkina Faso and southern Ghana had the highest number of anemic children.
What Do These Findings Mean?
These results add insight and detail to anemia prevalence and anemia severity within different geographical areas in three West African countries. The combination of anemia and mean hemoglobin predictive maps identifies communities in West Africa where preschool-age children are at increased risk of morbidity. The use of anemia maps has important practical implications for targeted control in these countries, such as guiding the efficient allocation of nutrient supplements and fortified foods, and enabling risk assessment of anemia due to different causes, which would in turn constitute an evidence base to calculate the best balance between interventions.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Abdisalan Noor
The WHO Web site has comprehensive information on the worldwide prevalence of anemia
More information on Demographic Health Surveys is available
More information on global predictions of malaria is available
PMCID: PMC3110251  PMID: 21687688
22.  Anemia and red blood cell transfusion in critically ill cardiac patients 
Anemia and red blood cell (RBC) transfusion occur frequently in hospitalized patients with cardiac disease. In this narrative review, we report the epidemiology of anemia and RBC transfusion in hospitalized adults and children (excluding premature neonates) with cardiac disease, and on the outcome of anemic and transfused cardiac patients. Both anemia and RBC transfusion are common in cardiac patients, and both are associated with mortality. RBC transfusion is the only way to rapidly treat severe anemia, but is not completely safe. In addition to hemoglobin (Hb) concentration, the determinant(s) that should drive a practitioner to prescribe a RBC transfusion to cardiac patients are currently unclear. In stable acyanotic cardiac patients, Hb level above 70 g/L in children and above 70 to 80 g/L in adults appears safe. In cyanotic children, Hb level above 90 g/L appears safe. The appropriate threshold Hb level for unstable cardiac patients and for children younger than 28 days is unknown. The optimal transfusion strategy in cardiac patients is not well characterized. The threshold at which the risk of anemia outweighs the risk of transfusion is not known. More studies are needed to determine when RBC transfusion is indicated in hospitalized patients with cardiac disease.
PMCID: PMC4085735  PMID: 25024880
Blood; Cardiac; Critical care; Erythrocyte; Hemoglobin; Intensive care; Practice; Risk factors; Surgery; Transfusion
23.  Metal-on-Metal Total Hip Resurfacing Arthroplasty 
Executive Summary
The objective of this review was to assess the safety and effectiveness of metal on metal (MOM) hip resurfacing arthroplasty for young patients compared with that of total hip replacement (THR) in the same population.
Clinical Need
Total hip replacement has proved to be very effective for late middle-aged and elderly patients with severe degenerative diseases of the hips. As indications for THR began to include younger patients and those with a more active life style, the longevity of the implant became a concern. Evidence suggests that these patients experience relatively higher rates of early implant failure and the need for revision. The Swedish hip registry, for example, has demonstrated a survival rate in excess of 80% at 20 years for those aged over 65 years, whereas this figure was 33% by 16 years in those aged under 55 years.
Hip resurfacing arthroplasty is a bone-conserving alternative to THR that restores normal joint biomechanics and load transfer. The technique has been used around the world for more than 10 years, specifically in the United Kingdom and other European countries.
The Technology
Metal-on-metal hip resurfacing arthroplasty is an alternative procedure to conventional THR in younger patients. Hip resurfacing arthroplasty is less invasive than THR and addresses the problem of preserving femoral bone stock at the initial operation. This means that future hip revisions are possible with THR if the initial MOM arthroplasty becomes less effective with time in these younger patients. The procedure involves the removal and replacement of the surface of the femoral head with a hollow metal hemisphere, which fits into a metal acetabular cup.
Hip resurfacing arthroplasty is a technically more demanding procedure than is conventional THR. In hip resurfacing, the femoral head is retained, which makes it much more difficult to access the acetabular cup. However, hip resurfacing arthroplasty has several advantages over a conventional THR with a small (28 mm) ball. First, the large femoral head reduces the chance of dislocation, so that rates of dislocation are less than those with conventional THR. Second, the range of motion with hip resurfacing arthroplasty is higher than that achieved with conventional THR.
A variety of MOM hip resurfacing implants are used in clinical practice. Six MOM hip resurfacing implants have been issued licences in Canada.
Review Strategy
A search of electronic bibliographies (OVID Medline, Medline In-Process and Other Non-Indexed Citations, Embase, Cochrane CENTRAL and DSR, INAHTA) was undertaken to identify evidence published from Jan 1, 1997 to October 27, 2005. The search was limited to English-language articles and human studies. The literature search yielded 245 citations. Of these, 11 met inclusion criteria (9 for effectiveness, 2 for safety).
The result of the only reported randomized controlled trial on MOM hip resurfacing arthroplasty could not be included in this assessment, because it used a cemented acetabular component, whereas in the new generation of implants, a cementless acetabular component is used. After omitting this publication, only case series remained.
Summary of Findings
Health Outcomes
The Harris hip score and SF-12 are 2 measures commonly used to report health outcomes in MOM hip resurfacing arthroplasty studies. Other scales used are the Oxford hip score and the University of California Los Angeles hip score.
The case series showed that the mean revision rate of MOM hip resurfacing arthroplasty is 1.5% and the incidence of femoral neck fracture is 0.67%. Across all studies, 2 cases of osteonecrosis were reported. Four studies reported improvement in Harris hip scores. However, only 1 study reported a statistically significant improvement. Three studies reported improvement in SF-12 scores, of which 2 reported a significant improvement. One study reported significant improvement in UCLA hip score. Two studies reported postoperative Oxford hip scores, but no preoperative values were reported.
None of the reviewed studies reported procedure-related deaths. Four studies reported implant survival rates ranging from 94.4% to 99.7% for a follow-up period of 2.8 to 3.5 years. Three studies reported on the range of motion. One reported improvement in all motions including flexion, extension, abduction-adduction, and rotation, and another reported improvement in flexion. Yet another reported improvement in range of motion for flexion abduction-adduction and rotation arc. However, the author reported a decrease in the range of motion in the arc of flexion in patients with Brooker class III or IV heterotopic bone (all patients were men).
Safety of Metal-on-Metal Hip Resurfacing Arthroplasty
There is a concern about metal wear debris and its systemic distribution throughout the body. Detectable metal concentrations in the serum and urine of patients with metal hip implants have been described as early as the 1970s, and this issue is still controversial after 35 years.
Several studies have reported high concentration of cobalt and chromium in serum and/or urine of the patients with metal hip implants. Potential toxicological effects of the elevated metal ions have heightened concerns about safety of MOM bearings. This is of particular concern in young and active patients in whom life expectancy after implantation is long.
Since 1997, 15 studies, including 1 randomized clinical trial, have reported high levels of metal ions after THR with metal implants. Some of these studies have reported higher metal levels in patients with loose implants.
Adverse Biological Effects of Cobalt and Chromium
Because patients who receive a MOM hip arthroplasty are shown to be exposed to high concentrations of metallic ions, the Medical Advisory Secretariat searched the literature for reports of adverse biological effects of cobalt and chromium. Cobalt and chromium make up the major part of the metal articulations; therefore, they are a focus of concern.
Risk of Cancer
To date, only one study has examined the incidence of cancer after MOM and polyethylene on metal total hip arthroplasties. The results were compared to that of general population in Finland. The mean duration of follow-up for MOM arthroplasty was 15.7 years; for polyethylene arthroplasty, it was 12.5 years. The standardized incidence ratio for all cancers in the MOM group was 0.95 (95% CI, 0.79–1.13). In the polyethylene on metal group it was 0.76 (95% CI, 0.68–0.86). The combined standardized incidence ratio for lymphoma and leukemia in the patients who had MOM THR was 1.59 (95% CI, 0.82–2.77). It was 0.59 (95% CI, 0.29–1.05) for the patients who had polyethylene on metal THR. Patients with MOM THR had a significantly higher risk of leukemia. All patients who had leukemia were aged over than 60 years.
Cobalt Cardiotoxicity
Epidemiological Studies of Myocardiopathy of Beer Drinkers
An unusual type of myocardiopathy, characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure, occurred as an epidemic affecting 48 habitual beer drinkers in Quebec City between 1965 and 1966. This epidemic was directly related the consumption of a popular beer containing cobalt sulfate. The epidemic appeared 1 month after cobalt sulfate was added to the specific brewery, and no further cases were seen a month after this specific chemical was no longer used in making this beer. A beer of the same name is made in Montreal, and the only difference at that time was that the Quebec brand of beer contained about 10 times more cobalt sulphate. Cobalt has been added to some Canadian beers since 1965 to improve the stability of the foam but it has been added in larger breweries only to draught beer. However, in small breweries, such as those in Quebec City, separate batches were not brewed for bottle and draught beer; therefore, cobalt was added to all of the beer processed in this brewery.
In March 1966, a committee was appointed under the chairmanship of the Deputy Minister of Health for Quebec that included members of the department of forensic medicine of Quebec’s Ministry of Justice, epidemiologists, members of Food and Drug Directorate of Ottawa, toxicologists, biomedical researchers, pathologists, and members of provincial police. Epidemiological studies were carried out by the Provincial Ministry of Health and the Quebec City Health Department.
The association between the development of myocardiopathy and the consumption of the particular brand of beer was proven. The mortality rate of this epidemic was 46.1% and those who survived were desperately ill, and recovered only after a struggle for their lives.
Similar cases were seen in Omaha (Nebraska). The epidemic started after a cobalt additive was used in 1 of the beers marketed in Nebraska. Sixty-four patients with the clinical diagnosis of alcoholic myocardiopathy were seen during an 18-month period (1964–1965). Thirty of these patients died. The first patient became ill within 1 month after cobalt was added to the beer, and the last patient was seen within 1 month of withdrawal of cobalt.
A similar epidemic occurred in Minneapolis, Minnesota. Between 1964 and 1967, 42 patients with acute heart failure were admitted to a hospital in Minneapolis, Minnesota. Twenty of these patients were drinking 6 to 30 bottles per day of a particular brand of beer exclusively. The other 14 patients also drank the same brand of beer, but not exclusively. The mortality rate from the acute illness was 18%, but late deaths accounted for a total mortality rate of 43%. Examination of the tissue from these patients revealed markedly abnormal changes in myofibrils (heart muscles), mitochondria, and sarcoplasmic reticulum.
In Belgium, a similar epidemic was reported in 1966, in which, cobalt was used in some Belgian beers. There was a difference in mortality between the Canadian or American epidemic and this series. Only 1 of 24 patients died, 1.5 years after the diagnosis. In March 1965, at an international meeting in Brussels, a new heart disease in chronic beer drinkers was described. This disease consists of massive pericardial effusion, low cardiac output, raised venous pressure, and polycythemia in some cases. This syndrome was thought to be different from the 2 other forms of alcoholic heart disease (beriberi and a form characterized by myocardial fibrosis).
The mystery of the above epidemics as stated by investigators is that the amount of cobalt added to the beer was below the therapeutic doses used for anemia. For example, 24 pints of Quebec brand of beer in Quebec would contain 8 mg of cobalt chloride, whereas an intake of 50 to 100 mg of cobalt as an antianemic agent has been well tolerated. Thus, greater cobalt intake alone does not explain the occurrence of myocardiopathy. It seems that there are individual differences in cobalt toxicity. Other features, like subclinical alcoholic heart disease, deficient diet, and electrolyte imbalance could have been precipitating factors that made these patients susceptible to cobalt’s toxic effects.
In the Omaha epidemic, 60% of the patients had weight loss, anorexia, and occasional vomiting and diarrhea 2 to 6 months before the onset of cardiac symptoms. In the Quebec epidemic, patients lost their appetite 3 to 6 months before the diagnosis of myocardiopathy and developed nausea in the weeks before hospital admission. In the Belgium epidemic, anorexia was one of the most predominant symptoms at the time of diagnosis, and the quality and quantity of food intake was poor. Alcohol has been shown to increase the uptake of intracoronary injected cobalt by 47%. When cobalt enters the cells, calcium exits; this shifts the cobalt to calcium ratio. The increased uptake of cobalt in alcoholic patients may explain the high incidence of cardiomyopathies in beer drinkers’ epidemics.
As all of the above suggest, it may be that prior chronic exposure to alcohol and/or a nutritionally deficient diet may have a marked synergistic effect with the cardiotoxicity of cobalt.
MOM hip resurfacing arthroplasty has been shown to be an effective arthroplasty procedure as tested in younger patients.
However, evidence for effectiveness is based only on 7 case series with short duration of follow-up (2.8–3.5 years). There are no RCTs or other well-controlled studies that compare MOM hip resurfacing with THR.
Revision rates reported in the MOM studies using implants currently licensed in Canada (hybrid systems, uncemented acetabular, and cemented femoral) range from 0.3% to 3.6% for a mean follow-up ranging from 2.8 to 3.5 years.
Fracture of femoral neck is not very common; it occurs in 0.4% to 2.2% of cases (as observed in a short follow-up period).
All the studies that measured health outcomes have reported improvement in Harris Hip and SF-12 scores; 1 study reported significant reduction in pain and improvement in function, and 2 studies reported significant improvement in SF-12 scores. One study reported significant improvement in UCLA Hip scores.
Concerns remain on the potential adverse effects of metal ions. Longer-term follow-up data will help to resolve the inconsistency of findings on adverse effects, including toxicity and carcinogenicity.
Ontario-Based Economic Analysis
The device cost for MOM ranges from $4,300 to $6,000 (Cdn). Traditional hip replacement devices cost about $2,000 (Cdn). Using Ontario Case Costing Initiative data, the total estimated costs for hip resurfacing surgery including physician fees, device fees, follow-up consultation, and postsurgery rehabilitation is about $15,000 (Cdn).
Cost of Total Hip Replacement Surgery in Ontario
MOM hip arthroplasty is generally recommended for patients aged under 55 years because its bone-conserving advantage enables patients to “buy time” and hence helps THRs to last over the lifetime of the patient. In 2004/2005, 15.9% of patients who received THRs were aged 55 years and younger. It is estimated that there are from 600 to 1,000 annual MOM hip arthroplasty surgeries in Canada with an estimated 100 to 150 surgeries in Ontario. Given the increased public awareness of this device, it is forecasted that demand for MOM hip arthroplasty will steadily increase with a conservative estimate of demand rising to 1,400 cases by 2010 (Figure 10). The net budget impact over a 5-year period could be $500,000 to $4.7 million, mainly because of the increasing cost of the device.
Projected Number of Metal-on-Metal Hip Arthroplasty Surgeries in Ontario: to 2010
PMCID: PMC3379532  PMID: 23074495
24.  Effect of anemia correction on left ventricular structure and filling pressure in anemic patients without overt heart disease 
There are few data on the effects of low hemoglobin levels on the left ventricle (LV) in patients without heart disease. The objective of this study was to document changes in the echocardiographic variables of LV structure and function after the correction of anemia without significant cardiovascular disease.
In total, 34 iron-deficiency anemia patients (35 ± 11 years old, 32 females) without traditional cardiovascular risk factors or cardiovascular disease and 34 age- and gender-matched controls were studied. Assessments included history, physical examination, and echocardiography. Of the 34 patients with anemia enrolled, 20 were followed and underwent echocardiography after correction of the anemia.
There were significant differences between the anemia and control groups in LV diameter, left ventricular mass index (LVMI), left atrial volume index (LAVI), peak mitral early diastolic (E) velocity, peak mitral late diastolic (A) velocity, E/A ratio, the ratio of mitral to mitral annular early diastolic velocity (E/E'), stroke volume, and cardiac index. Twenty patients underwent follow-up echocardiography after treatment of anemia. The follow-up results showed significant decreases in the LV end-diastolic and end-systolic diameters and LVMI, compared with baseline levels. LAVI, E velocity, and E/E' also decreased, suggesting a decrease in LV filling pressure.
Low hemoglobin level was associated with larger cardiac chambers, increased LV, mass and higher LV filling pressure even in the subjects without cardiovascular risk factors or overt cardiovascular disease. Appropriate correction of anemia decreased LV mass, LA volume, and E/E'.
PMCID: PMC4101591  PMID: 25045292
Anemia; Ventricular remodeling
25.  Nadir hemoglobin is associated with poor outcome from intracerebral hemorrhage 
SpringerPlus  2013;2:379.
Examine the relationship between anemia and outcomes from intracerebral hemorrhage (ICH).
Patients admitted with spontaneous ICH between July 2008 and December 2010 were identified from our prospective stroke registry. Patients were divided into two groups based on admission hemoglobin (low vs. normal based on laboratory reference range for gender). Baseline characteristics were compared between groups using Chi-square, t-tests and Wilcoxon Rank Sum tests. Primary outcome was functional status at discharge, with modified Rankin Scale (mRS) 5–6 considered a poor outcome. Cumulative logit and logistic regression models were used to assess the relationships between baseline hemoglobin, nadir hemoglobin, and transfusion with outcomes.
Of the 109 patients, 28% (n = 30) were anemic on admission. Baseline anemia did not predict the primary outcome. Nadir hemoglobin was associated with poor functional outcome at discharge (OR = 1.58, 95% CI 1.31-1.90, p < 0.0001) and remained significant after adjusting for age, baseline NIHSS, transfusion, and length of stay (OR = 1.43, 95% CI 1.06-1.94, p = 0.02). Patients who received a transfusion had 9 times greater odds of having a discharge mRS 5–6 (OR 9.37, 95% CI 2.84-30.88, p = 0.0002) compared with patients who did not receive transfusion. This was no longer statistically significant after adjusting for other factors impacting outcome (OR 4.01, 95% CI 0.64-25.32, p = 0.1392). Neither nadir hemoglobin nor transfusion was found to be independent predictors of in-hospital mortality.
This study suggests that nadir hemoglobin, not admission hemoglobin, can be used to predict poor functional outcome. Transfusion was not an independent predictor of poor outcome from ICH.
PMCID: PMC3755802  PMID: 24010037
Intracerebral hemorrhage; Anemia; Hemoglobin; Transfusion; Outcome

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