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1.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Background
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
Conclusions
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
Background
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000098.
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
2.  Red Blood Cell Transfusion and Mortality in Trauma Patients: Risk-Stratified Analysis of an Observational Study 
PLoS Medicine  2014;11(6):e1001664.
Using a large multicentre cohort, Pablo Perel and colleagues evaluate the association of red blood cell transfusion with mortality according to the predicted risk of death for trauma patients.
Please see later in the article for the Editors' Summary
Background
Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.
Methods and Findings
A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.
Conclusions
The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.
Trial registration
www.ClinicalTrials.gov NCT01746953
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Trauma—a serious injury to the body caused by violence or an accident—is a major global health problem. Every year, injuries caused by traffic collisions, falls, blows, and other traumatic events kill more than 5 million people (9% of annual global deaths). Indeed, for people between the ages of 5 and 44 years, injuries are among the top three causes of death in many countries. Trauma sometimes kills people through physical damage to the brain and other internal organs, but hemorrhage (serious uncontrolled bleeding) is responsible for 30%–40% of trauma-related deaths. Consequently, early trauma care focuses on minimizing hemorrhage (for example, by using compression to stop bleeding) and on restoring blood circulation after blood loss (health-care professionals refer to this as resuscitation). Red blood cell (RBC) transfusion is often used for the management of patients with trauma who are bleeding; other resuscitation products include isotonic saline and solutions of human blood proteins.
Why Was This Study Done?
Although RBC transfusion can save the lives of patients with trauma who are bleeding, there is considerable uncertainty regarding the balance of risks and benefits associated with this procedure. RBC transfusion, which is an expensive intervention, is associated with several potential adverse effects, including allergic reactions and infections. Moreover, blood supplies are limited, and the risks from transfusion are high in low- and middle-income countries, where most trauma-related deaths occur. In this study, which is a secondary analysis of data from a trial (CRASH-2) that evaluated the effect of tranexamic acid (which stops excessive bleeding) in patients with trauma, the researchers test the hypothesis that RBC transfusion may have a beneficial effect among patients at high risk of death following trauma but a harmful effect among those at low risk of death.
What Did the Researchers Do and Find?
The CRASH-2 trail included 20,127 patients with trauma and major bleeding treated in 274 hospitals in 40 countries. In their risk-stratified analysis, the researchers investigated the effect of RBC transfusion on CRASH-2 participants with a predicted risk of death (estimated using a validated model that included clinical variables such as heart rate and blood pressure) on admission to hospital of less than 6%, 6%–20%, 21%–50%, or more than 50%. That is, the researchers compared death rates among patients in each stratum of predicted risk of death who received a RBC transfusion with death rates among patients who did not receive a transfusion. Half the patients received at least one transfusion. Transfusion was associated with an increase in all-cause mortality at 28 days after trauma among patients with a predicted risk of death of less than 6% or of 6%–20%, but with a decrease in all-cause mortality among patients with a predicted risk of death of more than 50%. In absolute figures, compared to no transfusion, RBC transfusion was associated with 5.1 more deaths per 100 patients in the patient group with the lowest predicted risk of death but with 11.9 fewer deaths per 100 patients in the group with the highest predicted risk of death.
What Do These Findings Mean?
These findings show that RBC transfusion is associated with an increase in all-cause deaths among patients with trauma and major bleeding with a low predicted risk of death, but with a reduction in all-cause deaths among patients with a high predicted risk of death. In other words, these findings suggest that the effect of RBC transfusion on all-cause mortality may vary according to whether a patient with trauma has a high or low predicted risk of death. However, because the participants in the CRASH-2 trial were not randomly assigned to receive a RBC transfusion, it is not possible to conclude that receiving a RBC transfusion actually increased the death rate among patients with a low predicted risk of death. It might be that the patients with this level of predicted risk of death who received a transfusion shared other unknown characteristics (confounders) that were actually responsible for their increased death rate. Thus, to provide better guidance for clinicians caring for patients with trauma and hemorrhage, the hypothesis that RBC transfusion could be harmful among patients with trauma with a low predicted risk of death should be prospectively evaluated in a randomised controlled trial.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001664.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The World Health Organization provides information on injuries and on violence and injury prevention (in several languages)
The US Centers for Disease Control and Prevention has information on injury and violence prevention and control
The National Trauma Institute, a US-based non-profit organization, provides information about hemorrhage after trauma and personal stories about surviving trauma
The UK National Health Service Choices website provides information about blood transfusion, including a personal story about transfusion after a serious road accident
The US National Heart, Lung, and Blood Institute also provides detailed information about blood transfusions
MedlinePlus provides links to further resources on injuries, bleeding, and blood transfusion (in English and Spanish)
More information in available about CRASH-2 (in several languages)
doi:10.1371/journal.pmed.1001664
PMCID: PMC4060995  PMID: 24937305
3.  Identifying future ‘unexpected’ survivors: a retrospective cohort study of fatal injury patterns in victims of improvised explosive devices 
BMJ Open  2013;3(8):e003130.
Objectives
To identify potentially fatal injury patterns in explosive blast fatalities in order to focus research and mitigation strategies, to further improve survival rates from blast trauma.
Design
Retrospective cohort study.
Participants
UK military personnel killed by improvised explosive device (IED) blasts in Afghanistan, November 2007–August 2010.
Setting
UK military deployment, through NATO, in support of the International Security Assistance Force (ISAF) mission in Afghanistan.
Data sources
UK military postmortem CT records, UK Joint Theatre Trauma Registry and associated incident data.
Main outcome measures
Potentially fatal injuries attributable to IEDs.
Results
We identified 121 cases, 42 mounted (in-vehicle) and 79 dismounted (on foot), at a point of wounding. There were 354 potentially fatal injuries in total. Leading causes of death were traumatic brain injury (50%, 62/124 fatal injuries), followed by intracavity haemorrhage (20.2%, 25/124) in the mounted group, and extremity haemorrhage (42.6%, 98/230 fatal injuries), junctional haemorrhage (22.2%, 51/230 fatal injuries) and traumatic brain injury (18.7%, 43/230 fatal injuries) in the dismounted group.
Conclusions
Head trauma severity in both mounted and dismounted IED fatalities indicated prevention and mitigation as the most effective strategies to decrease resultant mortality. Two-thirds of dismounted fatalities had haemorrhage implicated as a cause of death that may have been anatomically amenable to prehospital intervention. One-fifth of the mounted fatalities had haemorrhagic trauma which currently could only be addressed surgically. Maintaining the drive to improve all haemostatic techniques for blast casualties, from point of wounding to definitive surgical proximal vascular control, alongside the development and application of novel haemostatic interventions could yield a significant survival benefit. Prospective studies in this field are indicated.
doi:10.1136/bmjopen-2013-003130
PMCID: PMC3733302  PMID: 23906957
Cause of Death; Battlefield Trauma; IED
4.  Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors 
PLoS Medicine  2012;9(1):e1001155.
Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism. They describe an ongoing elevated risk of death for individuals who had experienced a venous thrombosis or pulmonary embolism as compared to controls, for up to eight years after the event.
Background
Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis.
Methods and Findings
4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well.
736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0–24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0–5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7–4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0–6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories.
Conclusions
Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The term venous thrombosis describes the clinical situation—more common during pregnancy, after surgery, or serious illness—in which a blood clot lodges in a vein. One specific type, which is more serious, involves the clot forming in a major vein in the lower leg and thigh and is termed a deep venous thrombosis. The clot can block blood flow and cause swelling and pain, but more seriously, can break off and move through the bloodstream, causing an embolism. An embolism can get stuck in the brain (and cause a stroke), lungs (and cause a pulmonary embolism), heart (to cause a heart attack), and/or other areas of the body, leading to severe damage.
Venous thrombosis is known to be associated with considerable short-term morbidity and mortality: the mortality rate after venous thrombosis is about 20% within one year and studies to date have suggested that the mortality rate is two to four times higher for patients with pulmonary embolism, of whom 10%–20% die within three months after the event. Many factors are associated with venous thrombosis, and the underlying cause of the thrombosis affects survival; for example, those with thrombotic events provoked by surgery or trauma have a lower mortality risk than patients with thrombosis caused by malignancy. Furthermore, about 10%–20% of patients who have had a venous thrombosis develop a recurrence within five years and up to 50% develop post-thrombotic syndrome—long-term swelling, pain, and changes in skin color.
Why Was This Study Done?
It is currently unknown whether the poor prognosis associated with venous thrombosis is limited to the months following the thrombotic event, or persists for years afterwards. So in this study, the researchers sought to answer this question by analyzing the long-term survival in a large cohort of patients who had experienced a first venous thrombosis and who were all followed for up to eight years.
What Did the Researchers Do and Find?
The researchers used the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study), which was a case-control study involving 4,965 consecutive patients aged 18 to 70 years who were objectively diagnosed with a deep venous thrombosis or pulmonary embolism and recruited from six anticoagulation clinics in the Netherlands between March 1999 and September 2004. The control group consisted of partners of patients (n = 3,297) and a random control group matched on age and sex (n = 3,000). The researchers obtained causes of death from the Central Bureau of Statistics and for the observation period (30 days after the venous thrombosis, to either death or end of follow-up between February 2007 and May 2009) compared cause-specific death rates of the patients to those of the general Dutch population. The researchers devised specialist survival models (called Kaplan-Meier life-tables) and calculated standardized mortality ratios (SMRs—the ratio of the observed number of deaths over the number of deaths expected) to estimate relative rates of all cause mortality by type of the initial thrombosis and the underlying cause.
Using these methods, the researchers found that the overall mortality rate in patients with thrombosis was substantially greater than in the control group (22.7 per 1,000 person-years compared to 4.7 per 1,000 person-years). Apart from malignancies, the researchers found that the main causes of death were diseases of the circulatory and respiratory system. Patients with venous thrombosis and malignancy had the highest risk of mortality: 55% died during follow-up. Patients with venous thrombosis without malignancy had an overall 2-fold increased risk of mortality compared to the control group and this risk was comparable for patients with different forms of thrombosis (such as deep venous thrombosis and pulmonary embolus). According to the researchers' calculations, the relative risk of death was highest during the first three years after thrombosis, but for those with thrombosis of unknown cause, the risk of death increased by two-fold up to eight years after the thrombosis. Furthermore, the researchers found that the highly increased risk of death for those with pulmonary embolism is mainly only for the first month as long-term survival is similar to that of patients with a deep venous thrombosis.
What Do These Findings Mean?
These findings show that patients who have experienced a venous thrombosis for the first time have an increased risk of death, which may last up to eight years after the event. These findings have important clinical implications and suggest that long-term clinical follow-up could be beneficial in patients who have experienced a venous thrombosis for the first time.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001155.
Wikipedia provides information about venous thrombosis note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Medline has patient-friendly information about deep venous thrombosis and pulmonary embolism
doi:10.1371/journal.pmed.1001155
PMCID: PMC3254666  PMID: 22253578
5.  Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events? 
PLoS Medicine  2009;6(6):e1000099.
In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.
Background
Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.
Methods and Findings
In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70–82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44–2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04–1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).
Conclusions
In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the leading cause of death is coronary heart disease (CHD), a CVD in which narrowing of the heart's blood vessels by “atherosclerotic plaques” (fatty deposits that build up with age) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Other types of CVD include stroke (in which atherosclerotic plaques interrupt the brain's blood supply) and heart failure (a condition in which the heart cannot pump enough blood to the rest of the body). Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, and being overweight all increase a person's risk of developing CVD. Tools such as the “Framingham risk calculator” take these and other risk factors into account to assess an individual's overall risk of CVD, which can be reduced by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Inflammation (an immune response to injury) in the walls of blood vessels is thought to play a role in the development of atherosclerotic plaques. Consistent with this idea, several epidemiological studies (investigations of the causes and distribution of disease in populations) have shown that people with high circulating levels of markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen are more likely to have a stroke or a heart attack (a CVD event) than people with low levels of these markers. Although these studies have generally lumped together fatal and nonfatal CVD events, some evidence suggests that circulating inflammatory markers may be more strongly associated with fatal than with nonfatal CVD events. If this is the case, the mechanisms that lead to fatal and nonfatal CVD events may be subtly different and knowing about these differences could improve both the prevention and treatment of CVD. In this study, the researchers investigate this possibility using data collected in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER; a trial that examined pravastatin's effect on CVD development among 70–82 year olds with pre-existing CVD or an increased risk of CVD because of smoking, high blood pressure, or diabetes).
What Did the Researchers Do and Find?
The researchers used several statistical models to examine the association between baseline levels of IL-6, CRP, and fibrinogen in the trial participants and nonfatal CVD events (nonfatal heart attacks and nonfatal strokes), fatal CVD events, death from other types of CVD, and deaths from other causes during 3.2 years of follow-up. Increased levels of all three inflammatory markers were more strongly associated with fatal CVD than with nonfatal CVD after adjustment for treatment allocation and for other established CVD risk factors but this pattern was strongest for IL-6. Thus, a unit increase in the log of IL-6 levels increased the risk of fatal CVD by half but increased the risk of nonfatal CVD by significantly less. The researchers also investigated whether including these inflammatory markers in tools designed to predict an individual's CVD risk could improve the tool's ability to distinguish between individuals with a high and low risk. The addition of IL-6 to established risk factors, they report, increased this discriminatory ability for fatal CVD but not for nonfatal CVD.
What Do These Findings Mean?
These findings indicate that, at least for the elderly at-risk patients who were included in PROSPER, inflammatory markers are more strongly associated with the risk of a fatal heart attack or stroke than with nonfatal CVD events. These findings need to be confirmed in younger populations and larger studies also need to be done to discover whether the same association holds when fatal heart attacks and fatal strokes are considered separately. Nevertheless, the present findings suggest that inflammation may specifically help to promote the development of serious, potentially fatal CVD and should stimulate improved research into the use of inflammation markers to predict risk of deaths from CVD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000099.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and atherosclerosis (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
Information for patients and caregivers is provided by the American Heart Association on all aspects of cardiovascular disease, including information on inflammation and heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000099
PMCID: PMC2694359  PMID: 19554082
6.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
7.  Pesticide Use and Fatal Injury among Farmers in the Agricultural Health Study 
Purpose
To assess whether pesticide use practices were associated with injury mortality among 51,035 male farmers from North Carolina and Iowa enrolled in the Agricultural Health Study.
Methods
We used Cox proportional hazards models adjusted for age and state to estimate fatal injury risk associated with self-reported use of 49 specific pesticides, personal protective equipment, specific types of farm machinery, and other farm factors collected 1–15 years preceding death. Cause-specific mortality was obtained through linkage to mortality registries.
Results
We observed 338 injury fatalities over 727,543 person-years of follow-up (1993–2008). Fatal injuries increased with days per year of pesticide application, with the highest risk among those with 60+ days of pesticide application annually (Hazard Ratio (HR) =1.87; 95% Confidence Interval (CI) = 1.10, 3.18). Chemical-resistant glove use was associated with decreased risk (HR=0.73; 95%CI=0.58, 0.93), but adjusting for glove use did not substantially change estimates for individual pesticides or pesticide use overall. Herbicides were associated with fatal injury, even after adjusting for operating farm equipment, which was independently associated with fatal injury. Ever use of five of 18 herbicides (2,4,5–T, paraquat, alachlor, metribuzin, and butylate) were associated with elevated risk. In addition, 2,4–D and cyanazine were associated with fatal injury in exposure-response analyses. There was no evidence of confounding of these results by other herbicides.
Conclusion
The association between application of pesticides, particularly certain herbicides, and fatal injuries among farmers should be interpreted cautiously but deserves further evaluation, with particular focus on understanding timing of pesticide use and fatal injury.
doi:10.1007/s00420-012-0752-x
PMCID: PMC3515737  PMID: 22419121
pesticides; mortality; wounds; injuries
8.  Road Trauma in Teenage Male Youth with Childhood Disruptive Behavior Disorders: A Population Based Analysis 
PLoS Medicine  2010;7(11):e1000369.
Donald Redelmeier and colleagues conducted a population-based case-control study of 16-19-year-old males hospitalized for road trauma or appendicitis and showed that disruptive behavior disorders explained a significant amount of road trauma in this group.
Background
Teenage male drivers contribute to a large number of serious road crashes despite low rates of driving and excellent physical health. We examined the amount of road trauma involving teenage male youth that might be explained by prior disruptive behavior disorders (attention deficit hyperactivity disorder, conduct disorder, oppositional defiant disorder).
Methods and Findings
We conducted a population-based case-control study of consecutive male youth between age 16 and 19 years hospitalized for road trauma (cases) or appendicitis (controls) in Ontario, Canada over 7 years (April 1, 2002 through March 31, 2009). Using universal health care databases, we identified prior psychiatric diagnoses for each individual during the decade before admission. Overall, a total of 3,421 patients were admitted for road trauma (cases) and 3,812 for appendicitis (controls). A history of disruptive behavior disorders was significantly more frequent among trauma patients than controls (767 of 3,421 versus 664 of 3,812), equal to a one-third increase in the relative risk of road trauma (odds ratio  =  1.37, 95% confidence interval 1.22–1.54, p<0.001). The risk was evident over a range of settings and after adjustment for measured confounders (odds ratio 1.38, 95% confidence interval 1.21–1.56, p<0.001). The risk explained about one-in-20 crashes, was apparent years before the event, extended to those who died, and persisted among those involved as pedestrians.
Conclusions
Disruptive behavior disorders explain a significant amount of road trauma in teenage male youth. Programs addressing such disorders should be considered to prevent injuries.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In the latest World Health Organization (WHO) global burden of disease list, road traffic crashes are currently ranked eighth but are predicted to take fourth place by 2030 (by which time, road traffic deaths are likely to increase by more than 80% in developing countries and to decrease by nearly 30% in industrialized countries.) Every year, road traffic crashes kill an estimated 1.2 million people world-wide and injure or disable a further 20–60 million. Furthermore, the economic consequences of road traffic crashes account for about 2% of the gross national product of the entire global economy.
90% of road traffic deaths occur in developing countries where pedestrians, cyclists, and users of two-wheel vehicles (scooters, motorbikes) are the most vulnerable. In industrialized countries, teenage male drivers are the single most risky demographic group, with an incidence of road traffic crashes of twice that of the population average. Also, male teenagers are sometimes a hazard to other road users and contribute to more fatalities in older pedestrians than older drivers. Furthermore, teenage male drivers involved in serious crashes can have ongoing health care needs but are often resistant to standard road safety advice.
Why Was This Study Done?
Previous studies have suggested that disruptive behavior disorders might contribute to the risk of road traffic crashes in male teenagers but methodological problems with these studies make these results unclear. Given the importance of this topic, authorities have called for more research into the full range of behavioral disorders and relevant populations. This study attempted to avoid the methodological problems of previous studies and to rigorously assess whether disruptive behavior disorders predispose male teenagers to road traffic crashes.
What Did the Researchers Do and Find?
The researchers conducted a 7-year population-based case-control study in Ontario, Canada of consecutive male teenagers aged between 16 and 19 years who were admitted to a hospital due to a road traffic crash, including those who were pedestrians. For the controls, the researchers used consecutive males in the same age range who were admitted to the same hospitals during the same time interval for acute appendicitis (which is common and generally unrelated to traumatic injury). For each participant in the study, the authors used universal health care databases in Canada's single-payer health care system to identify relevant psychiatric diagnoses (attention deficit hyperactivity disorder, conduct disorder, and oppositional defiant disorder) during the decade before admission.
During the study period, 3,421 male teenagers were admitted to hospital as the result of a road traffic crash and 3,812 male teenagers were admitted to hospital for appendicitis. A history of disruptive behavior disorders was significantly more frequent among male teenagers admitted for road traffic crashes than controls (767 of 3,421 versus 664 of 3,812) giving an odds ratio 1.37. This higher risk was still present after the researchers adjusted for possible confounding factors (such as age, social status, and home location) and accounted for about one-in-20 road traffic crashes, including male teenagers who had died and those involved as pedestrians.
What Do These Findings Mean?
The results of this study suggest that disruptive behavior disorders explain a significant amount of road traffic crashes experienced in male teenagers. Overall, attention deficit hyperactivity disorder, conduct disorder, and oppositional defiant disorder are associated with about a one-third increase in the risk of a road traffic crash (which is similar to the relative risk among individuals treated for epilepsy.) As in previous studies in this area, some methodological problems may affect the interpretation of these findings. As this study did not document who was “at fault,” an alternative interpretation might be that behavioral disorders impair a teenager's ability to avoid a mishap initiated by someone else. Most importantly, the observed increase in risk as pedestrians indicates that male teenagers who abstain from driving do not escape the danger of road traffic crashes.
The researchers stress that any increased risk of road traffic crashes associated with disruptive behavior disorders in male teenagers does not justify withholding a driver's license, especially as many such disorders can be effectively treated or, indeed, because it does not address the issue of the increased risk for those teenagers who were pedestrians. Instead, they suggest that disruptive behavior disorders could be considered as contributors to road traffic crashes—analogous to seizure disorders and some other medical diseases. Therefore, greater attention by primary care physicians, psychiatrists, and community health workers might be helpful since interventions can perhaps reduce the risk including medical treatments and avoidance of distractions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000369.
The World Health Organization has information on road traffic crashes
The US National Institutes of Health has information about behavior disorders in children as well as UK-based Kids Development
The Ontarion Ministry of Transportation has information on annual roadway collisions in Ontario
doi:10.1371/journal.pmed.1000369
PMCID: PMC2981585  PMID: 21125017
9.  Pedestrian injury and the built environment: an environmental scan of hotspots 
BMC Public Health  2009;9:233.
Background
Pedestrian injury frequently results in devastating and costly injuries and accounts for 11% of all road user fatalities. In the United States in 2006 there were 4,784 fatalities and 61,000 injuries from pedestrian injury, and in 2007 there were 4,654 fatalities and 70,000 injuries. In Canada, injury is the leading cause of death for those under 45 years of age and the fourth most common cause of death for all ages Traumatic pedestrian injury results in nearly 4000 hospitalizations in Canada annually. These injuries result from the interplay of modifiable environmental factors. The objective of this study was to determine links between the built environment and pedestrian injury hotspots in Vancouver.
Methods
Data were obtained from the Insurance Corporation of British Columbia (ICBC) for the 6 year period from 2000 to 2005 and combined with pedestrian injury data extracted from the British Columbia Trauma Registry (BCTR) for the same period. High incident locations (hotspots) for pedestrian injury in the City of Vancouver were identified and mapped using geographic information systems (GIS), and the characteristics of the built environment at each of the hotspot locations were examined by a team of researchers.
Results
The analysis highlighted 32 pedestrian injury hotspot locations in Vancouver. 31 of 32 hotspots were situated on major roads. Likewise, the majority of hotspots were located on downtown streets. The 'downtown eastside' was identified as an area with multiple high-incident locations, including the 2 highest ranked pedestrian injury hotspots. Bars were present at 21 of the hotspot locations, with 11 of these locations being judged to have high alcohol establishment density.
Conclusion
This study highlighted the disproportionate burden of pedestrian injury centred on the downtown eastside area of Vancouver. The environmental scan revealed that important passive pedestrian safety countermeasures were only present at a minority of high-incident locations. More importantly, bars were highly associated with risk of pedestrian injury. This study is the basis for potential public health intervention by clearly indicating optimal locations for signalized pedestrian crosswalks.
doi:10.1186/1471-2458-9-233
PMCID: PMC2714512  PMID: 19602225
10.  Fatal pulmonary embolism in hospitalised medical patients. 
Journal of Clinical Pathology  1997;50(7):609-610.
This study aimed to determine the frequency of fatal pulmonary emboli in hospitalised medical patients by a retrospective necropsy review and prospective non-interventional patient follow up study. The main outcome measure, necropsy proven fatal pulmonary embolism, was determined from 400 consecutive necropsy records and 200 consecutive medical inpatient episodes. Fatal pulmonary embolism was recorded in 29 of 400 necropsies; 17 were medical patients. Thirty one of 200 consecutive medical patients died. Fourteen necropsies were performed and revealed pulmonary embolism as the cause of death in five patients. The incidence of necropsy proven fatal pulmonary embolism was therefore 2.5% (95% confidence intervals 0.8% to 5.7%). Therefore, one in 40 medical patients had pulmonary embolism recorded as the cause of death at necropsy. As the necropsy rate was only 45% the incidence of fatal pulmonary embolism may be greater. There is, therefore, a need to perform more large prospective studies to confirm the incidence of fatal pulmonary embolism in medical patients and to identify risk factors and effective antithrombotic prophylaxis.
PMCID: PMC500077  PMID: 9306945
11.  Injury to the diaphragm: Our experience in Union Head quarters Hospital 
Background:
Diaphragmatic injury is a global diagnostic and therapeutic challenge.
Objectives:
The study was to identify the variations in the risk factors, diagnosis, management, and outcome between blunt and penetrating injuries of the diaphragm.
Materials and Methods:
A prospective study was conducted on patients who were diagnosed with injury to diaphragm during preoperative, intraoperative, or postmortem period. The risk correlates and the trail of events following injury, interventions, and outcomes were studied.
Results:
Of the 25 cases, blunt injury was experienced by 10. Road traffic injury was the most common cause in blunt trauma and assault with knife in penetrating trauma. Acute presentation was the most common mechanism. X-rays were positive in 52% cases. The most common reason for false negative X-rays was massive effusion/hemothorax. Computed tomography (CT) improved the positivity rate to 62.5%. A total of 25% of diaphragmatic injuries were diagnosed during surgery for hemodynamic instability irrespective of initial X-rays findings. Laprotomy alone was sufficient in majority of cases. The defects were largely in the left side; mean defect size was more in blunt trauma. Associated injuries were noted in 92%. Stomach was most affected in penetrating injuries and spleen in blunt trauma. Empeyma was the most common morbidity. Mortality rate of 13% in penetrating injury was far lower than 60% in blunt injury. Mean Injury Severity Score (ISS) was significantly related to the fatal outcomes irrespective of mechanism. Diagnostic laparoscopy for asymptomatic low velocity junctional penetrating wounds revealed diaphragmatic injury in 20%.
Conclusions:
The incidence of multisystem injuries at our trauma center is on the rise. A high index of suspicion is needed for diagnosis of diaphragmatic injury. The need for thorough exploratory laprotomy is essential. In resource stretched setting like ours, the need for routine diagnostic laparoscopy in asymptomatic junctional wounds has to be validated further.
doi:10.4103/2229-5151.124139
PMCID: PMC3891192  PMID: 24459623
Blunt trauma; diaphragmatic injury; penetrating trauma; viscerthorax
12.  Violent and Fatal Youth Trauma: Is There a Missed Opportunity? 
Introduction
Accidents and assaults (homicides) are the leading causes of death among the youth of the United States, accounting for 53.3% of deaths among children aged 1 to19 years. Victim recidivism, defined as repeated visits to the emergency department (ED) as a victim of violent trauma, is a significantly growing public health problem. As 5-year mortality rates for recidivism are as high as 20%, it is important to determine whether victims with a history of violent trauma are at increased risk for fatal outcome with their next trauma. We hypothesized that victims of violent trauma who have had 1 prior ED visit for violent trauma will have increased odds of fatal outcome.
Methods
A retrospective chart review was conducted for patients presenting with penetrating trauma to the ED from January 1, 1999 to December 31, 2009. All patients between the ages of 15 to 25 years who presented to the ED for any penetrating trauma were included. Patients with prior presentations for penetrating trauma were compared to those patients who were first-time presenters to determine the odds ratio of fatal outcome.
Results
Overall, 15,395 patients were treated for traumatic presentations. Of these, 1,044 met inclusion criteria. Demographically, 79.4% were Hispanic, 19.4% were African American, and 0.96% were Caucasian. The average age was 21 years, and 98% of the population was male. One hundred and forty-seven (14%) had prior presentations, and 897 (86%) did not. Forty of the 147 patients (27%) with prior presentations had a fatal outcome as compared to 29 patients of the 868 (3%) without prior presentations, with odds ratio of 10.8 (95% confidence interval, 6.4–18.1; Pearson χ2, P < 0.001). The 5-year mortality rate for those patients with fatal outcomes was calculated at 16.5%.
Conclusion
Patients who had prior ED visits for penetrating trauma were at greater risk for fatal outcomes compared to those with no prior visits. Therefore, trauma-related ED visits might offer an opportunity for education and intervention. This may help to prevent future fatalities.
doi:10.5811/westjem.2011.6.6765
PMCID: PMC3415801  PMID: 22900103
13.  Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study 
PLoS Medicine  2011;8(9):e1001093.
By studying gene expression changes over time in a cohort of trauma patients, Keyur Desai and colleagues identify genes and pathways strongly associated with longer-term complications, which could lead to improved outcome prediction in the first 80 hours after injury.
Background
Trauma is the number one killer of individuals 1–44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition.
Methods and Findings
We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring ∼400 clinical variables and longitudinally profiling leukocyte gene expression with ∼800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40–80 h window post-injury.
Conclusions
The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions.
Trial Registration
ClinicalTrials.gov NCT00257231
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Trauma—a serious injury to the body caused by violence or by an accident—is a major global health problem. Every year, events that include traffic collisions, falls, blows, and fires cause injuries that kill more than 5 million people (9% of annual global deaths). Road traffic accidents alone are responsible for 1.3 million deaths a year and, if current trends continue, will be the fifth leading cause of death worldwide by 2030. Moreover, in many countries, including the US, trauma is the number one killer of individuals aged 1–44 y. Trauma can kill people rapidly through loss of blood or serious physical damage to internal organs, but it can also lead to localized infections and to sepsis, an infection of the bloodstream that is characterized by an amplified, body-wide (systemic) inflammatory response. Inflammation—redness, pain, and swelling—is an immune system response that normally provides protection against infections, but systemic inflammation can result in multiple organ failure (MOF) and death.
Why Was This Study Done?
Inflammatory complications of trauma are responsible for more than half of late trauma deaths, but at present it is impossible to predict which patients with major injuries will recover and which will spiral down into MOF and death, because the biological processes that underlie post-injury inflammatory complications are poorly understood. If the changes in gene expression (the process that converts the information encoded in genes into functional proteins) that accompany systemic inflammation could be elucidated, it might be possible to improve the diagnosis of MOF and to develop better treatments for post-trauma inflammatory complications. In this prospective, longitudinal clinical genomics study (part of the Inflammation and Host Response to Injury multi-disciplinary research program [IHRI]), the researchers developed an approach to associate early within-patient gene expression changes with later clinical outcomes. A prospective study is one in which patients with a specific condition are enrolled and then followed to see how various factors affect their outcomes; a longitudinal study analyzes multiple samples taken at different times from individual patients; a clinical genomics study investigates how genes and gene expression affect clinical outcomes.
What Did the Researchers Do and Find?
The researchers followed 168 patients for up to 28 d after they experienced blunt-force trauma (injuries caused when the human body hits or is hit by a large object such as a car). Using a molecular biology tool called a DNA microarray, they determined gene expression patterns in leukocytes (a type of immune system cell) isolated from multiple blood samples collected from each patient during the first few days after injury. Using clinical information collected by trained nurses, they organized the patients into five outcome categories based on a measure of MOF known as the Marshall score. Finally, they developed a statistical method (an analysis framework) to associate the early changes in gene expression with clinical outcomes.
A quarter of the patients' genes showed early expression changes that were associated with longer-term post-injury inflammatory complications. Among the associations revealed by this analysis, down-regulation (reduced expression) of MHC-class II genes (which encode proteins involved in antigen presentation, the process by which molecules from foreign invaders are presented to immune cells to initiate an immune response) and up-regulation of genes encoding components of the p38 MAPK signaling pathway (which helps to drive inflammatory responses) between 40 and 80 h post-injury were particularly strongly associated with longer-term post-injury complications and provided the strongest discrimination between patient outcomes.
What Do These Findings Mean?
The statistical approach used in this study to link the early changes in gene expression that occur after trauma to clinical outcomes provides a detailed picture of genome-wide gene expression responses to trauma. These findings could help scientists understand why some patients develop inflammatory complications of trauma while others do not, and they could help to identify those patients most at risk of developing complications. They could also help to identify targets for therapy, although further studies are needed to confirm and extend these findings. Importantly, the quantitative approach developed by the researchers for analyzing associations between within-patient gene changes over time and clinical outcomes should provide more robust predictions of outcomes than single measurements of gene expression and could be applicable to genomic studies of other rapidly progressing clinical conditions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001093.
More details about the Inflammation and Host Response to Injury research program are available; the program's website includes a link to an article that explains how genomics can be used to understand the inflammatory complications of trauma
The World Health Organization provides information on injuries and on violence and injury prevention (in several languages)
The US National Institutes of Health has a factsheet on burns and traumatic injury in the USA
The US Centers for Disease Control and Prevention has information on injury and violence prevention and control
MedlinePlus provides links to further resources on injuries
doi:10.1371/journal.pmed.1001093
PMCID: PMC3172280  PMID: 21931541
14.  Pediatric trauma deaths are predominated by severe head injuries during spring and summer 
Background
Trauma is the most prevalent cause of death in the young. Insight into cause and time of fatal pediatric and adolescent trauma is important for planning trauma care and preventive measures. Our aim was to analyze cause, severity, mode and seasonal aspects of fatal pediatric trauma.
Methods
Review of all consecutive autopsies for pediatric fatal trauma during a 10-year period within a defined population.
Results
Of all pediatric trauma deaths (n = 36), 70% were males, with the gender increasing with age. Median age was 13 years (range 2–17). Blunt trauma predominated (by road traffic accidents) with most (n = 15; 42%) being "soft" victims, such as pedestrians/bicyclist and, 13 (36%) drivers or passengers in motor vehicles.
Penetrating trauma caused only 3 deaths. Prehospital deaths (58%) predominated. 15 children (all intubated) reached hospital alive and had severely deranged vital parameters: 8 were hypotensive (SBP < 90 mmHg), 13 were in respiratory distress, and 14 had GCS < 8 on arrival. Emergency procedures were initiated (i.e. neurosurgical decompression, abdominal surgery or pelvic fixation for hemorrhage) in 12 patients. Probability of survival (Ps) was < 33% in over 75% of the fatalities. A bimodal death pattern was evident; the initial peak by CNS injuries and exsanguinations, the latter peak by CNS alone. Most fatalities occurred during spring (53%) or summertime (25%).
Conclusion
Fatal pediatric trauma occurs most frequently in boys during spring/summer, associated with severe head injuries and low probability of survival. Preventive measures appear mandated in order to reduce this mortality in this age group.
doi:10.1186/1757-7241-17-3
PMCID: PMC2637226  PMID: 19161621
15.  Venous thromboembolism after total joint arthroplasty: results from a Japanese multicenter cohort study 
Arthritis Research & Therapy  2014;16(4):R154.
Introduction
Real-world evidence of the effectiveness of pharmacological thromboprophylaxis for venous thromboembolism (VTE) is limited. Our objective was to assess the effectiveness and safety of thromboprophylactic regimens in Japanese patients undergoing joint replacement in a real-world setting.
Method
Overall, 1,294 patients (1,073 females and 221 males) who underwent total knee arthroplasty (TKA) and 868 patients (740 females and 128 males) who underwent total hip arthroplasty (THA) in 34 Japanese national hospital organization (NHO) hospitals were enrolled. The primary efficacy outcome was the incidence of deep vein thrombosis (DVT) detected by mandatory bilateral ultrasonography up to post-operative day (POD) 10 and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding (major or minor) and death from any cause up to POD28.
Results
Patients undergoing TKA (n = 1,294) received fondaparinux (n = 360), enoxaparin (n = 223), unfractionated heparin (n = 72), anti-platelet agents (n = 45), or no medication (n = 594). Patients undergoing THA (n = 868) received fondaparinux (n = 261), enoxaparin (n = 148), unfractionated heparin (n = 32), anti-platelet agents (n = 44), or no medication (n = 383). The incidence rates of sonographically diagnosed DVTs up to POD10 were 24.3% in patients undergoing TKA and 12.6% in patients undergoing THA, and the incidence rates of major bleeding up to POD28 were 1.2% and 2.3%, respectively. Neither fatal bleeding nor fatal pulmonary embolism occurred. Significant risk factors for postoperative VTE identified by multivariate analysis included gender (female) in both TKA and THA groups and use of a foot pump in the TKA group. Only prophylaxis with fondaparinux reduced the occurrence of VTE significantly in both groups. Propensity score matching analysis (fondaparinux versus enoxaparin) showed that the incidence of DVT was lower (relative risk 0.70, 95% confidence interval (CI) 0.58 to 0.85, P = 0.002 in TKA and relative risk 0.73, 95% CI 0.53 to 0.99, P = 0.134 in THA) but that the incidence of major bleeding was higher in the fondaparinux than in the enoxaparin group (3.4% versus 0.5%, P = 0.062 in TKA and 4.9% versus 0%, P = 0.022 in THA).
Conclusions
These findings indicate that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of DVT but increases bleeding tendency in patients undergoing TKA and THA.
Trial registration
University Hospital Medical Information Network Clinical Trials Registry: UMIN000001366. Registered 11 September 2008.
doi:10.1186/ar4616
PMCID: PMC4223565  PMID: 25047862
16.  Blood Glucose and Risk of Incident and Fatal Cancer in the Metabolic Syndrome and Cancer Project (Me-Can): Analysis of Six Prospective Cohorts 
PLoS Medicine  2009;6(12):e1000201.
Tanja Stocks and colleagues carry out an analysis of six European cohorts and confirm that abnormal glucose metabolism is linked with increased risk of cancer overall and at specific sites.
Background
Prospective studies have indicated that elevated blood glucose levels may be linked with increased cancer risk, but the strength of the association is unclear. We examined the association between blood glucose and cancer risk in a prospective study of six European cohorts.
Methods and Findings
The Metabolic syndrome and Cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included 274,126 men and 275,818 women. Mean age at baseline was 44.8 years and mean follow-up time was 10.4 years. Excluding the first year of follow-up, 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. We used Cox regression models to calculate relative risk (RR) for glucose levels, and included adjustment for body mass index (BMI) and smoking status in the analyses. RRs were corrected for regression dilution ratio of glucose. RR (95% confidence interval) per 1 mmol/l increment of glucose for overall incident cancer was 1.05 (1.01–1.10) in men and 1.11 (1.05–1.16) in women, and corresponding RRs for fatal cancer were 1.15 (1.07–1.22) and 1.21 (1.11–1.33), respectively. Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder, and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach.
Conclusions
Data from our study indicate that abnormal glucose metabolism, independent of BMI, is associated with an increased risk of cancer overall and at several cancer sites. Our data showed stronger associations among women than among men, and for fatal cancer compared to incident cancer.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Large prospective population-based research studies can have the power to discover new associations, and to verify previously proposed associations, between specific risk factors and the subsequent occurrence of disease. One such study, the “Me-Can” (Metabolic syndrome and Cancer project) is investigating associations between cancer incidence and a cluster of metabolic risk factors that make up metabolic syndrome: a large waistline; a high level of fats called triglycerides in the blood; a low level of “good” cholesterol; high blood pressure; and raised blood glucose (hyperglycemia). Here the researchers investigate the associations between one of these risk factors—raised blood glucose—and cancer. It is normal for blood glucose levels to vary before and after meals, but raised levels that persist long-term are known to lead to organ damage and severe complications. It is thought that more than 30% of cancer-related deaths could be prevented by modifying key risk factors, such as tobacco control, modifying diet, staying active, and limiting exposure to environmental risk factors.
Why Was This Study Done?
A previous large research study (including roughly 1.3 million men and women, conducted in Korea) has already evaluated the association between high blood glucose levels and cancer risk, and found that high blood glucose levels were linked with increased risk of cancer—both getting it and dying from it. Studies in European and US populations have also found a link, but they considered relatively small numbers of people and so these could not be used to calculate the risk with respect to specific cancer sites. The researchers carrying out the Me-Can project wanted to verify whether the associations reported in the Korean study also held true for European populations.
What Did the Researchers Do and Find?
The researchers identified 274,126 men and 275,818 women from existing health studies in Norway, Austria, and Sweden for whom data had been recorded on blood glucose level, height, and weight. For each participant a baseline measurement was defined, consisting of data from the first health examination, which had complete data (including a blood glucose measurement and whether the participant smoked). The participants were tracked via national registers for up to around 25 years after the baseline measurement but most commonly for around a decade. Any cancer diagnosis was recorded, whether the participant survived to the end of the study, and causes of death for participants who died during the study. The researchers analyzed the data to assess whether a higher blood glucose level was associated with increased risk of certain cancers, in both men and women. The researchers took weight for height, and smoking into account and adjusted for measurement error from additional blood glucose measurements. The researchers found that, overall, the higher the level of blood glucose, the higher the risk of getting and dying from cancer. Average normal blood glucose levels are about 5 mmol/l, also expressed as 5 mM or 90 mg/dl. For each additional 1 mmol/l increase in blood glucose level, the risk of getting cancer was increased by 5% for men and 11% for women.
What Do These Findings Mean?
The authors concluded that high blood glucose is associated with increased cancer risk. The results largely confirm findings from the Korean study, although there are some differences in the risks of cancers at some specific sites, which may be due to differences in the populations such as genetics, diet, and rates of smoking. Among the strengths of the study are its large sample size and that glucose were measured more than once for many individuals in the study. However, the study is limited in that the researchers did not have data on other possible factors such as genetics, physical activity, or dietary factors, which are linked to cancer incidence and also may be related to blood glucose levels. The researchers propose that controlling blood glucose may lower cancer risk in the population. Although this interpretation is consistent with the data, the study design cannot conclusively demonstrate a causal association between glucose levels and cancer risk.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000201.
The US National Cancer Institute provides online information and statistics on cancer, including risk factors for cancer
The American Heart Association provides information on sugars in the diet, including helpful hints on how to reduce the amount eaten
The UK's National Health Service's Change4Life campaign provides information and ideas for those wishing to make their lifestyle, including diet, more healthy
Cancer Research UK is the world's leading charity dedicated to beating cancer through research. Its websites provide information about cancer and the research it funds
doi:10.1371/journal.pmed.1000201
PMCID: PMC2791167  PMID: 20027213
17.  Patients with pelvic fractures due to falls: A paradigm that contributed to autopsy-based audit of trauma in Greece 
Background
Evaluation of the pelvic fractures (PFx) population in auditing effective components of trauma care is the subject of this study.
Methods
A retrospective, case-control, autopsy-based study compared a population with PFx to a control-group using a template with trauma outcome variables, which included demographics, ICD-9, intention, mechanisms, toxicology, Abbreviated Injury Scale (AIS-90), Injury Severity Score (ISS), causes of haemorrhage, comorbidity, survival time, pre-hospital response, in hospital data, location of death, and preventable deaths.
Results
Of 970 consecutive patients with fatal falls, 209 (21.5%) had PFx and constituted the PFx-group while 761 (78.5%) formed the control-group.
Multivariate analysis showed that gender, age, intention, and height of fall were risk factors for PFx. A 300% higher odds of a psychiatric history was found in the PFx-group compared to the control-group (p < 0.001).
The median ISS was 50 (17-75) for the PFx-group and 26 (1-75) for the control-group (p < 0.0001). There were no patients with an ISS less than 16 in the PFx group.
Associated injuries were significantly more common in the PFx-group than in the control-group. Potentially preventable deaths (ISS < 75) constituted 78% (n = 163) of the PFx-group. The most common AIS3-5 injuries in the potentially preventable subset of patients were the lower extremities in 133 (81.6%), thorax in 130 (79.7%), abdomen/pelvic contents in 99 (60.7%), head in 95 (58.3%) and the spine in 26 (15.9%) patients.
A subset of 126 (60.3%) potentially preventable deaths in the PFx-group had at least one AIS-90 code other than the PFx, denoting major haemorrhage. Deaths directly attributed to PFx were limited to 6 (2.9%).
The median survival time was 30 minutes for the PFx-group and 20 hours for the control-group (p < 0.001). For a one-group increment in the ISS-groups, the survival rates over the post-traumatic time intervals were reduced by 57% (p < 0.0001).
Pre-hospital mortality was significantly higher in the PFx-group i.e. 70.3% of the PFx-group versus 42.7% of the control-group (p < 0.001).
Conclusions
The PFx-group shared common causative risk factors, high severity and multiplicity of injuries that define the PFx-group as a paradigm of injury for audit. This reduced sample of autopsies substantially contributed to the audit of functional, infrastructural, management and prevention issues requiring transformation to reduce mortality.
doi:10.1186/1752-2897-5-2
PMCID: PMC3024215  PMID: 21214946
18.  Pattern of injury in fatal road traffic accidents in a rural area of western Maharashtra, India 
The Australasian Medical Journal  2013;6(9):476-482.
Background
Fatal road traffic accidents (RTA) are a major cause of concern all over the world. The outcome of injuries sustained in an RTA depends on various factors including but not limited to: the location of the event, type of vehicle involved, nature of the roads, the time of accident, etc.
Aims
This study aims to investigate and evaluate prospectively the socio-demographic profile and pattern of injuries in victims of RTA in the rural area of the Ahmedanagar district of Maharashtra state.
Method
This prospective study included all victims of RTA that presented to our emergency room from 1 June 2007 to 31 May 2009 and were either found dead on arrival or died during treatment. All the victims were autopsied at the post-mortem centre of Rural Medical College, Loni.
Results
Ninety-eight RTA victims were studied during the period. The most commonly affected age group was 20-39 years. Men died in RTA more than women. Fatal RTA were more prevalent on the secondary road system (47.97 per cent) and especially involved pedestrian and two wheeler vehicle users. Large numbers (n=63, 64.28%) of victims either died on the scene or during transportation. Numbers of skeletal injuries (199) and internal organ injuries (202) exceeded the total number of victims (98) clearly indicating the multiplicity of injuries. The majority of RTA victims (n=46, 46.93%) died due to head injury. The study showed that most deaths in RTA, brought to a tertiary care rural hospital, took place either on the spot or within 24 hours of injury which is very alarming and highlights the need to take urgent steps to establish good pre-hospital care and provision of trauma services at site.
Conclusion
A computerised trauma registry is urgently needed to highlight risk factors, circumstances and chains of events leading to accidents. This would be extremely helpful in policy making and health management in India.
doi:10.4066/AMJ.2013.1839
PMCID: PMC3794418  PMID: 24133540
Road traffic accidents; injuries; vehicles; rural
19.  Epidemiology of Trauma Patients and Analysis of 268 Mortality Cases: Trends of a Single Center in Korea 
Yonsei Medical Journal  2014;56(1):220-226.
Purpose
There is an increasing incidence of mortality among trauma patients; therefore, it is important to analyze the trauma epidemiology in order to prevent trauma death. The authors reviewed the trauma epidemiology retrospectively at a regional emergency center of Korea and evaluated the main factors that led to trauma-related deaths.
Materials and Methods
A total of 17007 trauma patients were registered to the trauma registry of the regional emergency center at Wonju Severance Christian Hospital in Korea from January 2010 to December 2012.
Results
The mean age of patients was 35.2 years old. The most frequent trauma mechanism was blunt injury (90.8%), as well as slip-and-fall down injury, motor vehicle accidents, and others. Aside from 142 early trauma deaths, a total of 4673 patients were admitted for further treatment. The most common major trauma sites of admitted patients were on the extremities (38.4%), followed by craniocerebral, abdominopelvis, and thorax. With deaths of 126 patients during in-hospital treatment, the overall mortality (142 early and 126 late deaths) was 5.6% for admitted patients. Ages ≥55, injury severity score ≥16, major craniocerebral injury, cardiopulmonary resuscitation at arrival, probability of survival <25% calculated from the trauma and injury severity score were independent predictors of trauma mortality in multivariate analysis.
Conclusion
The epidemiology of the trauma patients studied was found to be mainly blunt trauma. This finding is similar to previous papers in terms of demographics and mechanism. Trauma patients who have risk factors of mortality require careful management in order to prevent trauma-related deaths.
doi:10.3349/ymj.2015.56.1.220
PMCID: PMC4276759  PMID: 25510768
Trauma; epidemiology; mortality; injury severity score; predictor
20.  Paediatric trauma on the Last Frontier: an 11-year review of injury mechanisms, high-risk injury patterns and outcomes in Alaskan children 
International Journal of Circumpolar Health  2014;73:10.3402/ijch.v73.25066.
Background
Paediatric trauma system development in Alaska is complicated by a vast geographic coverage area, wide regional variations in environment and culture, and a lack of available published data.
Objective
To provide a detailed description of paediatric trauma mechanisms, high-risk injury patterns and outcomes in Alaska.
Design
This retrospective study included all children aged 17 years or younger in the State of Alaska Trauma Registry database admitted with traumatic injury between 2001 and 2011. Each injury record was reviewed individually and assigned a mechanism based on Centers for Disease Control E-codes. Geographic definitions were based on existing Emergency Medical Services regions. Mechanisms were compared by geographic region, patient demographics, injury characteristics and outcome. Subgroup analysis of fatal injuries was performed to identify causes of death.
Results
Of 5,547 patients meeting inclusion criteria, the most common mechanisms of injury were falls (39%), motor vehicle collisions (10%) and all-terrain vehicle (ATV) accidents (9%). The overall case fatality rate was 2%. Mechanisms with the greatest risk of death were gunshot wounds (21%), pedestrians struck by motorized vehicles (9%) and motor vehicle collisions (5%). These 3 mechanisms accounted for 15% of injuries but 60% of deaths in the overall cohort. Injury patterns involving combined central nervous system (CNS) and torso injuries were unusual but especially lethal, occurring in 3% of patients but carrying a case fatality rate of 18%. Although the distribution of mechanisms was generally similar for each geographic region, ATV and snowmobile injuries were significantly more common in remote areas (23% remote vs. 7% non-remote, p < 0.0001).
Conclusions
Mechanisms of paediatric trauma in Alaska have widely varying impacts on outcome and show some variation by region. Highest-risk mechanisms include gunshot wounds and motorized vehicle-related accidents. Prevention efforts should give special attention to CNS injury prevention, ATV and snowmobile safety in remote areas, and optimization of management of multisystem trauma. Further studies should investigate predictors of outcome in greater detail.
doi:10.3402/ijch.v73.25066
PMCID: PMC4125707  PMID: 25147771
Alaska; injury; epidemiology; youth; resource utilization
21.  Skinfold thickness, body mass index, and fatal coronary heart disease: 30 year follow up of the Northwick Park heart study 
Study objective
To examine the effect of baseline body mass index (BMI) and skinfold thickness (ST) on fatal coronary heart disease (CHD) and all cause mortality after 30 years of follow up.
Design
Prospective cohort study.
Setting
Northwick Park heart study (NPHS) designed to investigate the role of haemostatic variables on CHD.
Participants
1511 men and 691 women enrolled in NPHS aged 40 to 64 years at entry.
Main results
Baseline BMI (kg/m2) and forearm, triceps, subscapular, and suprailiac skinfolds ST (mm) were measured. Cox regression was used to calculate hazard ratios for fatal CHD and total mortality for each standard deviation unit increase in obesity adjusting for age, smoking status, total cholesterol, systolic blood pressure, fibrinogen, and factor VII activity. Subjects experienced 250 fatal CHDs and 819 all cause deaths over 30 years (median: 26 years; IQR: 22–28 years). Among men, only BMI (RR = 1.29, 95%CI = 1.12 to 1.49) significantly increased the risk of fatal CHD. Among women, BMI (RR = 1.48, 95%CI = 1.07 to 2.06), as well as, subscapular (RR = 1.65, 95%CI = 1.19 to 2.30), forearm (RR = 1.46, 95%CI = 1.08 to 1.97), and triceps (RR = 1.63, 95%CI = 1.12 to 2.39) skinfolds were predictive of fatal CHD. None of the estimates for all cause mortality were significant except for subscapular skinfold in women (RR = 1.20, 95%CI = 1.02 to 1.42). There was no evidence of interaction between obesity and sex for fatal CHD or all cause death. The effect of obesity on fatal CHD or all cause deaths does not seem to be mediated substantially by cholesterol, systolic blood pressure, or haemostatic variables.
Conclusions
BMI is an important risk factor for fatal CHD where its prognostic significance remains after up to 30 years of follow up.
doi:10.1136/jech.2005.042200
PMCID: PMC2465571  PMID: 16476761
coronary heart disease; obesity; body mass index; skinfold thickness; mortality
22.  Is Glycaemia or Insulin Dose the Stronger Risk Factor for Coronory Artery Disease (CAD) in Type 1 Diabetes? 
Though Coronary Artery Disease (CAD) is the leading cause of death in Type 1 Diabetes (T1D), the mechanisms responsible for the greatly increased risk are poorly understood. In particular the role of glycaemic control is controversial with one study suggesting it predicts CAD mortality but not incidence. In this analysis, of the Pittsburgh Epidemiology of Diabetes Complications study cohort of T1D, we examine whether risk factors differ for CAD morbidity and mortality, with a specific focus on HbA1c and insulin dose.
Participants (n=592) were followed for 18 years for incident non-fatal and fatal CAD. Cox stepwise regression was used to determine the independent risk factors for non-fatal and fatal CAD.
Mean age and diabetes duration at study baseline were 29 and 20 years, respectively. There were 109 incident non-fatal and 48 fatal CAD events. Baseline HbA1c was an independent risk factor for fatal CAD, along with duration of diabetes and albuminuria.
In contrast, baseline lower insulin dose was strongly predictive of non-fatal CAD, as was lower renal function, higher diastolic blood pressure, and lipids.
HbA1c predicts CAD mortality while lower insulin dose and standard CAD risk factors predict CAD morbidity.
doi:10.1177/1479164109336041
PMCID: PMC2865431  PMID: 20368215
23.  Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial 
Objectives To examine whether the effect of tranexamic acid on the risk of death and thrombotic events in patients with traumatic bleeding varies according to baseline risk of death. To assess the extent to which current protocols for treatment with tranexamic acid maximise benefits to patients.
Design Prespecified stratified analysis of data from an international multicentre randomised controlled trial (the CRASH-2 trial) with an estimation of the proportion of premature deaths that could potentially be averted through the administration of tranexamic acid.
Participants 13 273 trauma patients in the CRASH-2 trial who were treated with tranexamic acid or placebo within three hours of injury and trauma patients enrolled in UK Trauma and Audit Research Network, stratified by risk of death at baseline (<6%, 6-20%, 21-50%, >50%).
Intervention Tranexamic acid (1 g over 10 minutes followed by 1 g over eight hours) or matching placebo.
Main outcome measure Odds ratios and 95% confidence intervals for death in hospital within four weeks of injury, deaths from bleeding, and fatal and non-fatal thrombotic events associated with the use of tranexamic acid according to baseline risk of death. Unless there was strong evidence against the null hypothesis of homogeneity of effects (P<0.001), the overall odds ratio was used as the most reliable guide to the odds ratios in all strata.
Results Tranexamic acid was associated with a significant reduction in all cause mortality and deaths from bleeding. In each stratum of baseline risk, there were fewer deaths among patients treated with tranexamic acid. There was no evidence of heterogeneity in the effect of tranexamic acid on all cause mortality (P=0.96 for interaction) or deaths from bleeding (P=0.98) by baseline risk of death. In those treated with tranexamic acid there was a significant reduction in the odds of fatal and non-fatal thrombotic events (odds ratio 0.69, 95% confidence interval 0.53 to 0.89; P=0.005) and a significant reduction in arterial thrombotic events (0.58, 0.40 to 0.83; P=0.003) but no significant reduction in venous thrombotic events (0.83, 0.59 to 1.17; P=0.295). There was no evidence of heterogeneity in the effect of tranexamic acid on the risk of thrombotic events (P=0.74). If the effect of tranexamic acid is assumed to be the same in all risk strata (<6%, 6-20%, 21-50%, >50% risk of death at baseline), the percentage of deaths that could be averted by administration of tranexamic acid within three hours of injury in each group is 17%, 36%, 30%, and 17%, respectively.
Conclusions Tranexamic acid can be administered safely to a wide spectrum of patients with traumatic bleeding and should not be restricted to the most severely injured.
Trial registration ISRCTN86750102.
doi:10.1136/bmj.e5839
PMCID: PMC3439642  PMID: 22968527
24.  Obesity and smoking are factors associated with poor prognosis in patients with bacteraemia 
Background
Bacteraemia is still a major cause of case fatality in all age groups. Our aim was to identify the major underlying conditions constituting risk factors for case fatality in bacteraemia patients.
Methods
The study involved 149 patients (79 male and 70 female) with bacteraemia caused by Staphylococcus aureus (S. aureus) (41 patients), Streptococcus pneumoniae (Str. pneumoniae) (42 patients), β-hemolytic streptococcae (β-hml str.) (23 patients) and Eschericia coli (E. coli) (43 patients). Underlying diseases, alcohol and tobacco consumption and body mass index (BMI) were registered. Laboratory findings and clinical data were registered on admission and 6 consecutive days and on day 10–14. Case fatality was studied within 30 days after positive blood culture. Associations between underlying conditions and case fatality were studied in univariate analysis and in a multivariate model.
Results
Nineteen patients (12.8%) died of bacteraemia. We found obesity (p = 0.002, RR 9.8; 95% CI 2.3 to 41.3), smoking (p < 0.001, RR 16.9; 95% CI 2.1 to 133.5), alcohol abuse (p = 0.008, RR 3.9; 95% CI 1.3 to 11.28), COPD (p = 0.01, RR 8.4; 95% CI 1.9 to 37.1) and rheumatoid arthritis (p = 0.045, RR 5.9; 95% CI 1.2 to 28.8) to be significantly associated with case fatality in bacteraemia in univariate model. The median BMI was significantly higher among those who died compared to survivors (33 vs. 26, p = 0.003). Obesity and smoking also remained independent risk factors for case fatality when their effect was studied together in a multivariate model adjusted with the effect of alcohol abuse, age (continuos variable), sex and causative organism.
Conclusion
Our results indicate that obesity and smoking are prominent risk factors for case fatality in bacteraemic patients. Identification of risk factors underlying fatal outcome in bacteraemia may allow targeting of preventive efforts to individuals likely to derive greatest potential benefit.
doi:10.1186/1471-2334-7-13
PMCID: PMC1831474  PMID: 17349033
25.  Do inclusive trauma systems improve outcomes following renal trauma? 
Background
Our aim is to assess state variation in renal trauma outcomes. We hypothesize that states with more hospitals participating in a trauma system will have lower nephrectomy and mortality rates.
Methods
The Heathcare Cost and Utilization Project State Inpatient Database was utilized to conduct a retrospective cohort study of all patients hospitalized with renal injury from partnering states during 2001, 2004, and 2007. State trauma systems were categorized based on the proportion of all acute care hospitals designated as a trauma center (level I-V), with higher proportions correlating to a more inclusive system. Poisson regression for relative risks of inpatient nephrectomy and case fatality were performed adjusting for patient and state level factors.
Results
Patients in states with the “most inclusive” trauma systems had a 30% lower risk of nephrectomy (RR 0.70 95% CI 0.56, 0.88) and a 2.06% lower unadjusted inpatient case fatality rate compared to states with “exclusive” trauma systems. Inpatient case fatality risk varied significantly by trauma system inclusiveness. Patients treated in states with either a “more inclusive” (RR 0.85, 95% CI 0.74, 0.97) or “most inclusive” (0.74, 95% CI 0.64, 0.85) trauma system were independently associated with a lower inpatient case fatality risk compared to states with “exclusive” systems.
Conclusions
A reduced risk of nephrectomy and inpatient case fatality are more common among states that have a higher proportion of acute care hospitals participating as a trauma center (level I-V). Standardization of care may correlate with improved patient outcomes following renal trauma.
doi:10.1097/TA.0b013e3182411c67
PMCID: PMC3281515  PMID: 22327981
renal trauma; nephrectomy; outcomes; tiered delivery of trauma care

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