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1.  The NLstart2run study: health effects of a running promotion program in novice runners, design of a prospective cohort study 
BMC Public Health  2013;13:685.
Background
Running is associated with desirable lifestyle changes. Therefore several initiatives have been undertaken to promote running. Exact data on the health effects as a result of participating in a short-term running promotion program, however, is scarce. One important reason for dropout from a running program is a running-related injury (RRI). The incidence of RRIs is high, especially in novice runners. Several studies examined potential risk factors for RRIs, however, due to the often underpowered studies it is not possible to reveal the complex mechanism leading to an RRI yet.
The primary objectives are to determine short- and long-term health effects of a nationwide “Start to Run” program and to identify determinants for RRIs in novice runners. Secondary objectives include examining reasons and determinants for dropout, medical consumption and economical consequences of RRIs as a result of a running promotion program.
Methods/design
The NLstart2run study is a multi-center prospective cohort study with a follow-up at 6, 12, 24 and 52 weeks. All participants that sign up for the Start to Run program in 2013, which is offered by the Dutch Athletics Federation, will be asked to participate in the study.
During the running program a digital running log will be completed by the participants every week to administer exposure and running related pain. After the running program the log will be completed every second week. An RRI is defined as any musculoskeletal ailment of the lower extremity or back that the participant attributed to running and hampers running ability for at least one week.
Discussion
The NLstart2run study will provide insight into the short- and long-term health effects as a result of a short-term running promotion program. Reasons and determinants for dropout from a running promotion program will be examined as well. The study will result in several leads for future RRI prevention and as a result minimize dropout due to injury. This information may increase the effectiveness of future running promotion programs and will thereby contribute positively to public health.
Trial registration
The Netherlands National Trial Register NTR3676. The NTR is part of the WHO Primary Registries.
doi:10.1186/1471-2458-13-685
PMCID: PMC3849042  PMID: 23890182
2.  The GRONORUN 2 study: effectiveness of a preconditioning program on preventing running related injuries in novice runners. The design of a randomized controlled trial 
Background
Distance running is a popular recreational exercise. It is a beneficial activity for health and well being. However, running may also cause injuries, especially of the lower extremities. In literature there is no agreement what intrinsic and extrinsic factors cause running related injuries (RRIs). In theory, most RRIs are elicited by training errors, this too much, too soon. In a preconditioning program runners can adapt more gradually to the high mechanical loads of running and will be less susceptible to RRIs. In this study the effectiveness of a 4-week preconditioning program on the incidence of RRIs in novice runners prior to a training program will be studied.
Methods/Design
The GRONORUN 2 (Groningen Novice Running) study is a two arm randomized controlled trial studying the effect of a 4-week preconditioning (PRECON) program in a group of novice runners. All participants wanted to train for the recreational Groningen 4-Mile running event. The PRECON group started a 4-week preconditioning program with walking and hopping exercises 4 weeks before the start of the training program. The control (CON) and PRECON group started a frequently used 9-week training program in preparation for the Groningen 4-Mile running event.
During the follow up period participants registered their running exposure, other sporting activities and running related injuries in an Internet based running log. The primary outcome measure was the number of RRIs. RRI was defined as a musculoskeletal ailment or complaint of the lower extremities or back causing a restriction on running for at least three training sessions.
Discussion
The GRONORUN 2 study will add important information to the existing running science. The concept of preconditioning is easy to implement in existing training programs and will hopefully prevent RRIs especially in novice runners.
Trial registration
The Netherlands National Trial Register NTR1906. The NTR is part of the WHO Primary Registries.
doi:10.1186/1471-2474-11-196
PMCID: PMC2936887  PMID: 20809930
3.  NO ASSOCIATION BETWEEN Q-ANGLE AND FOOT POSTURE WITH RUNNING-RELATED INJURIES: A 10 WEEK PROSPECTIVE FOLLOW-UP STUDY 
Background/Purpose:
There is a paucity of knowledge on the association between different foot posture quantified by Foot Posture Index (FPI) and Quadriceps angle (Q-angle) with development of running-related injuries. Earlier studies investigating these associations did not include an objective measure of the amount of running performed.
Therefore, the purpose of this study was to investigate if kilometers to running-related injury (RRI) differ among novice runners with different foot postures and Q-angles when running in a neutral running shoe.
Methods:
A 10 week study was conducted including healthy, novice runners. At baseline foot posture was evaluated using the foot posture index (FPI) and the Q-angle was measured. Based on the FPI and Q-angle, right and left feet / knees of the runners were categorized into exposure groups. All participants received a Global Positioning System watch to allow them to quantify running volume and were instructed to run a minimum of two times per week in a conventional, neutral running shoe. The outcome was RRI.
Results:
Fifty nine novice runners of mixed gender were included. Of these, 13 sustained a running-related injury. No significant difference in cumulative relative risk between persons with pronated feet and neutral feet was found after 125 km of running (Cumulative relative risk = 1.65 [0.65; 4.17], p = 0.29). Similarly, no difference was found between low and neutral Q-angle (Cumulative relative risk = 1.25 [0.49; 3.23], p = 0.63).
Conclusion:
Static foot posture as quantified by FPI and knee alignment as quantified by Q-angle do not seem to affect the risk of injury among novice runners taking up a running regimen wearing a conventional neutral running shoe. These results should be interpreted with caution due to a small sample size.
Level of Evidence:
2a
PMCID: PMC3812840  PMID: 24175127
Foot posture; foot Posture Index; novice runners; running-related injuries; Q-angle
4.  Bone mineral density and serum testosterone in chronically trained, high mileage 40–55 year old male runners 
Objectives—To identify physical activity that is beneficial for the maintenance of bone strength with increasing age by examining the relation between bone mineral density (BMD) and chronic endurance training in men. BMD at the proximal femur, its subregions, and the lumbar spine, and serum testosterone were compared between two groups of long distance runners with more than 20 years of training experience and non-athletic controls.
Methods—Runners (n = 12) were divided into (a) high volume runners (n = 7), running 64–80 km a week, and (b) very high volume runners (n = 5), running more than 95 km a week, and compared with non-athletic male controls, exercising in non-endurance oriented activities two to four times a week. BMD (g/cm2) at the total proximal femur, femoral neck, trochanteric region, and lumbar spine was measured by dual energy x ray absorptiometry. Total testosterone (nmol/l) and free testosterone (pmol/l) in serum were measured by radioimmunoassay from single fasting blood samples.
Results—Height, weight, and age (range = 40–55 years) were not significantly different between groups. The high volume runners had significantly higher BMD at the total proximal femur (1.09 (0.17) v 0.94 (0.056)), femoral neck (0.91 (0.16) v 0.78 (0.071)), and trochanteric region (0.85 (0.14) v 0.73 (0.053)) than controls (p<0.05). The differences in BMD for the proximal femur between the very high volume runners and the other two groups were not significant. There was no difference in lumbar spine BMD, total testosterone, or free testosterone between groups. However, there was a significant negative correlation between total testosterone (r = -0.73, p<0.01) and free testosterone (r = -0.79, p<0.005) and running volume in the distance runners.
Conclusions—Long term distance running with training volumes less than 80 km a week had a positive effect on BMD of the proximal femur. With running volumes greater than 64 km a week, training was inversely related to testosterone levels, but levels remained within the normal range.
Key Words: exercise; bone mineral density; male athletes; runners; endurance training; testosterone
doi:10.1136/bjsm.34.4.273
PMCID: PMC1724199  PMID: 10953900
5.  Pre- and postmarathon training habits of nonelite runners 
Background
Despite the increasing popularity of marathons, little research has examined the training habits of nonelite marathon runners. Given that nonelite runners, particularly those with a competitive motive, have a higher risk for injury than experienced elite runners, it is important for physicians to understand the training program and features that might distinguish running performance and injury rates in this population.
Hypothesis:
We hypothesized that nonelite runners who qualify for the Boston Marathon (“qualifers”) would have higher running volumes, more running sessions per week, lower injury rates, and lower body mass index (BMI) than nonqualifying runners.
Study design:
A cross-sectional Web-based survey of runners (convenience sample) at 1 month (n = 50) and 6 months (n = 41) after participation in the 2008 Twin Cities Marathon (TCM) that acquired data on anthropometric measures, demographic data, finishing time, premarathon/current training program, and self-reported injury.
Results
Thirteen of 50 initial survey respondents were classified as a “qualifier” based on their finishing time. Mean BMI was significantly lower in the qualifiers at 1 month (22.0 versus 23.9 kg/m2, P = 0.0267) but not 6 months postmarathon. There were no significant differences in training volume (running frequency, run length, or cross-training volume) or injury rates between qualifiers and nonqualifiers. Prior to the 2008 TCM, 54% of runners included cross-training in their exercise program, which increased significantly to 74% 1 month postmarathon (P = 0.0039) and 71% 6 months postmarathon (P = 0.0325). There was no association between cross-training and injury rates.
Conclusions
Nonelite marathon runners had a high degree of cross-training in their training program. Qualifiers for the Boston Marathon did not significantly differ in running frequency, run length, or cross-training volume compared with nonqualifiers. Whether changes in the training program at an individual level might facilitate a change in qualifying status remains to be determined.
doi:10.2147/OAJSM.S16665
PMCID: PMC3781877  PMID: 24198565
training; marathon; cross-training; BMI
6.  Effect of foot orthoses on lower extremity kinetics during running: a systematic literature review 
Background
Throughout the period of one year, approximately 50% of recreational runners will sustain an injury that disrupts their training regimen. Foot orthoses have been shown to be clinically effective in the prevention and treatment of several running-related conditions, yet the physical effect of this intervention during running remains poorly understood. The aim of this literature review was therefore to evaluate the effect of foot orthoses on lower extremity forces and pressure (kinetics) during running.
Methods
A systematic search of electronic databases including Medline (1966-present), CINAHL, SportDiscus, and The Cochrane Library occurred on 7 May 2008. Eligible articles were selected according to pre-determined criteria. Methodological quality was evaluated by use of the Quality Index as described by Downs & Black, followed by critical analysis according to outcome variables.
Results
The most widely reported kinetic outcomes were loading rate and impact force, however the effect of foot orthoses on these variables remains unclear. In contrast, current evidence suggests that a reduction in the rearfoot inversion moment is the most consistent kinetic effect of foot orthoses during running.
Conclusion
The findings of this review demonstrate systematic effects that may inform the direction of future research, as further evidence is required to define the mechanism of action of foot orthoses during running. Continuation of research in this field will enable targeting of design parameters towards biomechanical variables that are supported by evidence, and may lead to advancements in clinical efficacy.
doi:10.1186/1757-1146-1-13
PMCID: PMC2611967  PMID: 19014705
7.  Fine structure of the low-frequency spectra of heart rate and blood pressure 
BMC Physiology  2003;3:11.
Background
The aim of this study was to explore the principal frequency components of the heart rate and blood pressure variability in the low frequency (LF) and very low frequency (VLF) band. The spectral composition of the R–R interval (RRI) and systolic arterial blood pressure (SAP) in the frequency range below 0.15 Hz were carefully analyzed using three different spectral methods: Fast Fourier transform (FFT), Wigner-Ville distribution (WVD), and autoregression (AR). All spectral methods were used to create time–frequency plots to uncover the principal spectral components that are least dependent on time. The accurate frequencies of these components were calculated from the pole decomposition of the AR spectral density after determining the optimal model order – the most crucial factor when using this method – with the help of FFT and WVD methods.
Results
Spectral analysis of the RRI and SAP of 12 healthy subjects revealed that there are always at least three spectral components below 0.15 Hz. The three principal frequency components are 0.026 ± 0.003 (mean ± SD) Hz, 0.076 ± 0.012 Hz, and 0.117 ± 0.016 Hz. These principal components vary only slightly over time. FFT-based coherence and phase-function analysis suggests that the second and third components are related to the baroreflex control of blood pressure, since the phase difference between SAP and RRI was negative and almost constant, whereas the origin of the first component is different since no clear SAP–RRI phase relationship was found.
Conclusion
The above data indicate that spontaneous fluctuations in heart rate and blood pressure within the standard low-frequency range of 0.04–0.15 Hz typically occur at two frequency components rather than only at one as widely believed, and these components are not harmonically related. This new observation in humans can help explain divergent results in the literature concerning spontaneous low-frequency oscillations. It also raises methodological and computational questions regarding the usability and validity of the low-frequency spectral band when estimating sympathetic activity and baroreflex gain.
doi:10.1186/1472-6793-3-11
PMCID: PMC270047  PMID: 14552660
8.  WEEKLY RUNNING VOLUME AND RISK OF RUNNING‐RELATED INJURIES AMONG MARATHON RUNNERS 
Purpose/Background:
The purpose of this study was to investigate if the risk of injury declines with increasing weekly running volume before a marathon race.
Methods:
The study was a retrospective cohort study on marathon finishers. Following a marathon, participants completed a web‐based questionnaire. The outcome of interest was a self‐reported running‐related injury. The injury had to be severe enough to cause a reduction in distance, speed, duration or frequency of running for at least 14 days. Primary exposure was self‐reported average weekly volume of running before the marathon categorized into below 30 km/week, 30 to 60 km/week, and above 60 km/week.
Results:
A total of 68 of the 662 respondents sustained an injury. When adjusting for previous injury and previous marathons, the relative risk (RR) of suffering an injury rose by 2.02 [95% CI: 1.26; 3.24], p < 0.01, among runners with an average weekly training volume below 30 km/week compared with runners with an average weekly training volume of 30‐60 km/week. No significant differences were found between runners exceeding 60 km/week and runners running 30‐60 km/week (RR=1.13 [0.5;2.8], p=0.80).
Conclusions:
Runners may be advised to run a minimum of 30 km/week before a marathon to reduce their risk of running‐related injury.
Level of Evidence:
2b
PMCID: PMC3625790  PMID: 23593549
Running‐related injury; marathon; risk factors; running volume.
9.  The GRONORUN study: is a graded training program for novice runners effective in preventing running related injuries? Design of a Randomized Controlled Trial 
Background
Running is a popular form of recreational exercise. Beside the positive effects of running on health and fitness, the risk of a running related injury has to be considered. The incidence of injuries in runners is high and varies from 30–79%. However, few intervention studies on prevention of running related injuries have been performed and none of these studies involved novice runners.
Methods
GRONORUN (Groningen Novice Running) is a two armed randomized controlled trial, comparing the effects of two different training programs for novice runners on the incidence of running related injuries. Participants are novice runners, who want to train for a four mile running event. The control group will train according a standard 8 week training program. The intervention group will use a more gradual, 13 week training program which is based on "the ten percent training rule". During the thirteen week follow up participants register information on running and RRI's in an internet based running log. The primary outcome measure is RRI. An injury is defined as a musculoskeletal ailment of the lower extremity or back, causing a restriction of running for at least one week.
Discussion
The GRONORUN trial is the first randomized controlled trial to study a preventive intervention in novice runners. Many different training programs for novice runners are offered, but none are evidence based.
doi:10.1186/1471-2474-8-24
PMCID: PMC1821023  PMID: 17331264
10.  Daily Physical Activity and Physical Fitness in 11-to 15-year-old Trained and Untrained Turkish Boys 
The aims of this study were to assess levels and patterns of physical activity (PA) in relation to age and regular sport activity, and to examine its relationship to physical fitness in trained and untrained boys. One hundred forty-seven 11-to 15- year-old boys (73 trained and 74 untrained) participated in this study. Trained boys, comprised of 26 soccer, 25 handball and 22 volleyball players, had been training regularly for at least one year. The intensity, duration and frequency of PA were assessed from four complete days of heart rate monitoring with 15-seconds sampling intervals. Aerobic fitness was assessed by determining peakVO2 with a portable breath-by-breath gas analyzer (Cosmed K4b2) and the running speeds at fixed lactate concentrations during an incremental running test. Anaerobic fitness was evalu-ated with the Wingate Anaerobic Test. Skinfold thicknesses from eight sites and Tanner stages of pubic hair were also obtained. Based on 15-s heart rate data, instead of continuous activity, multiple short bouts of moderate and vigorous PA, lasting up to one minute, were characteristic of daily PA patterns of both trained and untrained boys. PA levels of trained boys were higher than untrained boys (p < 0.01) and the levels of PA decreased with age and maturation in both groups (p < 0.05). Daily PA variables were related to body fatness in both groups (p < 0.05), but the relationships were not consistent in the trained group. Daily PA variables were also related to aerobic fitness in the untrained group (p < 0.05) and these relationships were somewhat better with vigorous PA, whereas in the trained group, none of the PA variables were related to any of the aerobic fitness indices (p > 0.05). No relationship was observed between PA variables and anaerobic fitness in either group (p> 0.05). It seems that such relationships may somewhat depend on the fitness level of the subjects.
Key pointsPA levels of trained boys were higher than untrained boys and the levels of PA decreased with age and maturation in both groups.Based on the 15-s HR data, instead of continuous activity, multiple short bouts of moderate and vigorous PA, lasting up to one minute, were characteristic of daily PA patterns of both trained and untrained boys.Daily PA variables were related to aerobic fitness in the untrained group and these relationships were somewhat better with vigorous PA (>70% HRR), whereas in the trained group, none of the PA variables were related to any of the aerobic fitness indices.Neither peak nor mean power values were related to any of the daily PA variables in both trained and untrained groups.
PMCID: PMC3737813  PMID: 24150625
Physical activity; training; aerobic and anaerobic fitness; body fatness; children
11.  The Redistribution of Power: Neurocardiac Signaling, Alcohol and Gender 
PLoS ONE  2011;6(12):e28281.
Human adaptability involves interconnected biological and psychological control processes that determine how successful we are in meeting internal and environmental challenges. Heart rate variability (HRV), the variability in consecutive R-wave to R-wave intervals (RRI) of the electrocardiogram, captures synergy between the brain and cardiovascular control systems that modulate adaptive responding. Here we introduce a qualitatively new dimension of adaptive change in HRV quantified as a redistribution of spectral power by applying the Wasserstein distance with exponent 1 metric (W1) to RRI spectral data. We further derived a new index, D, to specify the direction of spectral redistribution and clarify physiological interpretation. We examined gender differences in real time RRI spectral power response to alcohol, placebo and visual cue challenges. Adaptive changes were observed as changes in power of the various spectral frequency bands (i.e., standard frequency domain HRV indices) and, during both placebo and alcohol intoxication challenges, as changes in the structure (shape) of the RRI spectrum, with a redistribution towards lower frequency oscillations. The overall conclusions from the present study are that the RRI spectrum is capable of a fluid and highly flexible response, even when oscillations (and thus activity at the sinoatrial node) are pharmacologically suppressed, and that low frequency oscillations serve a crucial but less studied role in physical and mental health.
doi:10.1371/journal.pone.0028281
PMCID: PMC3229550  PMID: 22164260
12.  A systematic review of interventions to prevent lower limb soft tissue running injuries 
Objectives—To assess the available evidence for preventive strategies for lower limb soft tissue injuries caused by running.
Methods—An electronic database search was conducted using The Cochrane Musculoskeletal Injuries Group Specialised Register, The Cochrane Controlled Trials Register, Medline, Embase, Sport Discus, Heracles, Atlantes, Biosis, Cinahl, Scisearch, Current Contents, Index To Theses and Dissertation Abstracts. Any randomised or quasi-randomised trials evaluating interventions to prevent running injuries to lower limb soft tissue were included. The eligibility of trials for inclusion and the quality of the trials were independently assessed by two reviewers.
Results—Exposure to a high training load (duration, frequency, or running distance) increases the risk of injury, and thus modification of the training schedule can reduce the incidence of injury. The effectiveness of stretching exercises and of insoles in the prevention of lower extremity soft tissue injuries caused by running is not known. Wearing a knee brace with a patellar support ring may be effective in the prevention of anterior knee pain caused by running.
Conclusions—This review provides evidence for the effectiveness of the modification of training schedules in reducing lower limb soft tissue running injuries. More studies are required to quantify the optimal training loads and to confirm that knee braces can prevent knee pain. It is important to note that the studies included in this review had few female participants therefore the results may not be generalisable.
Key Words: running; lower limb; soft tissue; knee; ankle
doi:10.1136/bjsm.35.6.383
PMCID: PMC1724431  PMID: 11726471
13.  Measuring the Population Burden of Injuries—Implications for Global and National Estimates: A Multi-centre Prospective UK Longitudinal Study 
PLoS Medicine  2011;8(12):e1001140.
Ronan Lyons and colleagues compared the population burden of injuries using different approaches from the UK Burden of Injury and Global Burden of Disease studies and find that the absolute UK burden of injury is higher than previously estimated.
Background
Current methods of measuring the population burden of injuries rely on many assumptions and limited data available to the global burden of diseases (GBD) studies. The aim of this study was to compare the population burden of injuries using different approaches from the UK Burden of Injury (UKBOI) and GBD studies.
Methods and Findings
The UKBOI was a prospective cohort of 1,517 injured individuals that collected patient-reported outcomes. Extrapolated outcome data were combined with multiple sources of morbidity and mortality data to derive population metrics of the burden of injury in the UK. Participants were injured patients recruited from hospitals in four UK cities and towns: Swansea, Nottingham, Bristol, and Guildford, between September 2005 and April 2007. Patient-reported changes in quality of life using the EQ-5D at baseline, 1, 4, and 12 months after injury provided disability weights used to calculate the years lived with disability (YLDs) component of disability adjusted life years (DALYs). DALYs were calculated for the UK and extrapolated to global estimates using both UKBOI and GBD disability weights. Estimated numbers (and rates per 100,000) for UK population extrapolations were 750,999 (1,240) for hospital admissions, 7,982,947 (13,339) for emergency department (ED) attendances, and 22,185 (36.8) for injury-related deaths in 2005. Nonadmitted ED-treated injuries accounted for 67% of YLDs. Estimates for UK DALYs amounted to 1,771,486 (82% due to YLDs), compared with 669,822 (52% due to YLDs) using the GBD approach. Extrapolating patient-derived disability weights to GBD estimates would increase injury-related DALYs 2.6-fold.
Conclusions
The use of disability weights derived from patient experiences combined with additional morbidity data on ED-treated patients and inpatients suggests that the absolute burden of injury is higher than previously estimated. These findings have substantial implications for improving measurement of the national and global burden of injury.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Injuries—resulting from traffic collisions, drowning, poisoning, falls or burns, and violence from assault, self-inflicted violence, or acts of war—kill more than 5 million people worldwide every year and cause harm to millions more. Injuries account for at least 9% of global mortality and are a threat to health in every country of the world. Furthermore, for every death-related injury, dozens of injured people are admitted to hospitals, hundreds visit emergency rooms, and thousands go to see their doctors by appointment. A large proportion of people surviving their injuries will be left with temporary or permanent disabilities.
The Global Burden of Diseases, Injuries and Risk Factors (GBD) Studies are instrumental in quantifying the burden of injuries placed on society and are essential for the public health response, priority setting, and policy development. Central to the GBD methodology is the concept of Disability Adjusted Life years (DALYs), and a combination of premature mortality, referred to as years of life lost and years lived with disability. However, rather than evidence and measurements, the GBD Study used panel studies and expert opinion to estimate weights and durations of disability. Therefore, although the GBD has been a major development, it may have underestimated the population burden.
Why Was This Study Done?
Accurate measurement of the burden of injuries is essential to ensure adequate policy responses to prevention and treatment. In this study, the researchers aimed to overcome the limitations of previous studies and for the first time, measured the population burden of injuries in the UK using a combination of disability and morbidity metrics, including years of life lost, and years lived with disabilities.
What Did the Researchers Do and Find?
The researchers recruited patients aged over 5 years with a wide range of injuries (including fractures and dislocations, lacerations, bruises and abrasions, sprains, burns and scalds, and head, eye, thorax, and abdominal injuries) from hospitals in four English cities—Swansea, Nottingham, Bristol, and Guildford—between September 2005 and April 2007. The researchers collected data on injury-related mortality, hospital admissions, and attendances to emergency rooms. They also invited patients (or their proxy, if participants were young children) to complete a self-administered questionnaire at recruitment and at 1, 4, and 12 months postinjury to allow data collection on injury characteristics, use of health and social services, time off work, and recovery from injury, in addition to sociodemographic and economic and occupational characteristics. The researchers also used standardized tools to measure health-related quality of life and work problems. Then, the researchers used these patient-reported changes to calculate DALYs for the UK and then extrapolated these results to calculate global estimates.
In the four study sites, a total of 1,517 injured people (median age of 37.4 years and 53.9% male) participated in the study. The researchers found that the vast majority of injuries were unintentional and that the home was the most frequent location of injury. Using the data and information collected from the questionnaires, the researchers extrapolated their results and found that in 2005, there were an estimated 750,999 injury-related hospital admissions, 7,982,947 emergency room attendances, and 22,185 injury-related deaths, translating to a rate per 100,000 of 1,240, 13,339, and 36.8, respectively. The researchers estimated UK DALYs related to injury to be 1,771,486 compared with 669,822 using the GBD approach. Furthermore, the researchers found that extrapolating patient-derived disability weights to GBD estimates would increase injury-related DALYs 2.6-fold.
What Do These Findings Mean?
The findings of this study suggest that, when using data and information derived from patient experiences, combined with additional morbidity data on patients treated in emergency rooms and those, admitted to hospital, the absolute burden of injury is higher than previously estimated. While this study was carried out in the UK the principal findings are relevant to other countries. However, measurement of the population burden of injuries requires access to high quality data, which may be difficult in less affluent countries, and these data rely on access to health facilities, which is often restricted in resource-limited settings. Despite these concerns, these findings have substantial implications for improving measurements of the national and global burden of injury.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001140.
The World Health Organization website provides detailed information about injuries and also details the work of the Global Burden of Disease Study
The Global Burden of Injury's website is a portal to websites run by groups conducting ongoing research into the measurement of global injury metrics
doi:10.1371/journal.pmed.1001140
PMCID: PMC3232198  PMID: 22162954
14.  A prospective study of running injuries: the Vancouver Sun Run "In Training" clinics 
Objectives: Seventeen running training clinics were investigated to determine the number of injuries that occur in a running programme designed to minimise the injury rate for athletes training for a 10 km race. The relative contributions of factors associated with injury were also reported.
Methods: A total of 844 primarily recreational runners were surveyed in three trials on the 4th, 8th, and 12th week of the 13 week programme of the "In Training" running clinics. Participants were classified as injured if they experienced at least a grade 1 injury—that is, pain only after running. Logistic regression modelling and odds ratio calculation were performed for each sex using the following predictor variables: age, body mass index (BMI), previous aerobic activity, running frequency, predominant running surface, arch height, running shoe age, and concurrent cross training.
Results: Age played an important part in injury in women: being over 50 years old was a risk factor for overall injury, and being less than 31 years was protective against new injury. Running only one day a week showed a non-significant trend for injury risk in men and was a significant risk factor in women and overall injury. A BMI of > 26 kg/m2 was reported as protective for men. Running shoe age also significantly contributed to the injury model. Half of the participants who reported an injury had had a previous injury; 42% of these reported that they were not completely rehabilitated on starting the 13 week training programme. An injury rate of 29.5% was recorded across all training clinics surveyed. The knee was the most commonly injured site.
Conclusions: Although age, BMI, running frequency (days a week), and running shoe age were associated with injury, these results do not take into account an adequate measure of exposure time to injury, running experience, or previous injury and should thus be viewed accordingly. In addition, the reason for the discrepancy in injury rate between these 17 clinics requires further study.
doi:10.1136/bjsm.37.3.239
PMCID: PMC1724633  PMID: 12782549
15.  Effect of Body Mass Index on Breast Cancer during Premenopausal and Postmenopausal Periods: A Meta-Analysis 
PLoS ONE  2012;7(12):e51446.
Objective
There is no universal consensus on the relationship between body mass index (BMI) and breast cancer. This meta-analysis was conducted to estimate the overall effect of overweight and obesity on breast cancer risk during pre- and post-menopausal period.
Data Sources
All major electronic databases were searched until April 2012 including Web of Knowledge, Medline, Scopus, and ScienceDirect. Furthermore, the reference lists and related scientific conference databases were searched.
Review Methods
All prospective cohort and case-control studies investigating the association between BMI and breast cancer were retrieved irrespective of publication date and language. Women were assessed irrespective of age, race and marital status. The exposure of interest was BMI. The primary outcome of interest was all kinds of breast cancers confirmed pathologically. Study quality was assessed using the checklist of STROBE. Study selection and data extraction were performed by two authors separately. The effect measure of choice was risk ratio (RRi) and rate ratio (RRa) for cohort studies and odds ratio (OR) in case-control studies.
Results
Of 9163 retrieved studies, 50 studies were included in meta-analysis including 15 cohort studies involving 2,104,203 subjects and 3,414,806 person-years and 35 case-control studies involving 71,216 subjects. There was an inverse but non-significant correlation between BMI and breast cancer risk during premenopausal period: OR = 0.93 (95% CI 0.86, 1.02); RRi = 0.97 (95% CI 0.82, 1.16); and RRa = 0.99 (95% CI 0.94, 1.05), but a direct and significant correlation during postmenopausal period: OR = 1.15 (95% CI 1.07, 1.24); RRi = 1.16 (95% CI 1.08, 1.25); and RRa = 0.98 (95% CI 0.88, 1.09).
Conclusion
The results of this meta-analysis showed that body mass index has no significant effect on the incidence of breast cancer during premenopausal period. On the other hand, overweight and obesity may have a minimal effect on breast cancer, although significant, but really small and not clinically so important.
doi:10.1371/journal.pone.0051446
PMCID: PMC3517558  PMID: 23236502
16.  Nutritional indicators for gastrointestinal symptoms in female runners: the ‘Marikenloop study’ 
BMJ Open  2014;4(8):e005780.
Objectives
Among runners the reported prevalence of exercise-induced gastrointestinal (GI) symptoms is high (25%–83%). We aimed to investigate the prevalence of GI symptoms in women during a 5–10 km run in general and to explore the association between nutritional intakes and GI symptoms.
Setting
As part of the Marikenloop-study (a cohort study to identify predictor variables of running injuries), a cross-sectional questionnaire was distributed in interested runners of the ‘2013 Marikenloop’.
Participants
433 female runners filled in the questionnaire.
Primary and secondary outcome measures
The primary outcome measure was the frequency of running-related GI symptoms during running in general and during the last (training) run. Furthermore, dietary intake was determined before and during this run. Secondary outcome measures were several demographic and anthropometric variables.
Results
During running in general, 40% of the participants suffered from GI symptoms and during their last run, 49%. The GI symptoms side ache, flatulence, urge to defecate and regurgitation and/or belching were most commonly reported. Lower age (OR=0.98, 95% CI 0.96 to 1.00), minor running experience (OR=3.1, 95% CI 1.7 to 5.7), higher body mass index (OR=1.1, 95% CI 1.0 to 1.2), consuming carbohydrate-containing drinks during running (OR=10.5, 95% CI 1.4 to 80.3) and experiencing GI symptoms during running in general OR=5.0, 95% CI 3.2 to 7.8) significantly contributed to GI symptoms during the last run in the logistic regression analysis. In contrast, time of eating and carbohydrate-containing drinks consumed prior to the run were not related to GI symptoms.
Conclusions
In conclusion, the current study confirms the high prevalence of GI symptoms in female runners. Several predictor variables contributed to the GI symptoms but more research is needed to specify the effects of prerunning eating and carbohydrate-containing drinks on GI symptoms during running.
Trial registration number
Marikenloop study 2013: 50-50310-98-156 (ZonMw).
doi:10.1136/bmjopen-2014-005780
PMCID: PMC4127936  PMID: 25091016
GASTROENTEROLOGY; SPORTS MEDICINE
17.  Lack of Association of Estrogen Receptor Alpha Gene Polymorphisms with Cardiorespiratory and Metabolic Variables in Young Women 
This study examined the association of estrogen receptor alpha gene (ESR1) polymorphisms with cardiorespiratory and metabolic parameters in young women. In total, 354 healthy women were selected for cardiopulmonary exercise testing and short-term heart rate (HR) variability (HRV) evaluation. The HRV analysis was determined by the temporal indices rMSSD (square root of the mean squared differences of successive R–R intervals (RRi) divided by the number of RRi minus one), SDNN (root mean square of differences from mean RRi, divided by the number of RRi) and power spectrum components by low frequency (LF), high frequency (HF) and LF/HF ratio. Blood samples were obtained for serum lipids, estradiol and DNA extraction. ESR1 rs2234693 and rs9340799 polymorphisms were analyzed by PCR and fragment restriction analysis. HR and oxygen uptake (VO2) values did not differ between the ESR1 polymorphisms with respect to autonomic modulation. We not find a relationship between ESR1 T–A, T–G, C–A and C–G haplotypes and cardiorespiratory and metabolic variables. Multiple linear regression analysis demonstrated that VO2, total cholesterol and triglycerides influence HRV (p < 0.05). The results suggest that ESR1 variants have no effect on cardiorespiratory and metabolic variables, while HRV indices are influenced by aerobic capacity and lipids in healthy women.
doi:10.3390/ijms131013691
PMCID: PMC3497348  PMID: 23202974
estrogen receptor-α gene polymorphisms; heart rate variability; aerobic capacity; lipids
18.  Mood, mileage and the menstrual cycle. 
Forty women took part in a study to determine the effects of high-intensity training and the menstrual cycle on mood states. Half of the sample were competitive distance runners following a training load of between 50 km and 130 km running per week. Seven athletes were amenorrhoeic and 13 either eumenorrhoeic or oligomenorrhoeic. The remaining 20 subjects were inactive women who menstruated regularly. The mean age of all 40 subjects was 29 years. Each subject completed two identical Profile of Mood States (POMS) questionnaires. The 33 menstruating subjects completed both a premenstrual and a midcycle form and the amenorrhoeic athletes completed the questionnaires at a 3-week interval, which acted as a control for the potential effects of premenstrual syndrome (PMS) among the menstruating females. Results showed highly significant differences in mood profiles among amenorrhoeic athletes, non-amenorrhoeic athletes and inactive women. The greatest difference was between premenstrual and midcycle measures for the inactive group. PMS appears to cause marked negative mood swings among menstruating women which the POMS inventory is sensitive in detecting. While the lower-intensity-training runners appeared to benefit psychologically from a training distance of approximately 50 km week-1, high-intensity training had an adverse effect on mood.
PMCID: PMC1478953  PMID: 1422649
19.  CLASSIFYING RUNNING‐RELATED INJURIES BASED UPON ETIOLOGY, WITH EMPHASIS ON VOLUME AND PACE 
Background and Purpose:
Many researchers acknowledge the importance of “training errors” as the main cause of running‐related injuries. The purpose of this clinical commentary is to present a theoretical framework for the assumption that some running‐related injuries among rear‐foot strikers develop due to rapidly changing running volume, while others develop due to rapidly changing running pace.
Description of Topic with Related Evidence:
Evidence from clinical and experimental studies is presented to support the assertion that rapid change in running volume may lead to the development of patellofemoral pain syndrome, iliotibial band syndrome, and patellar tendinopathy, while change in running pace may be associated with the development of achilles tendinopathy, gastrocnemius injuries, and plantar fasciitis.
Discussion/Relation to Clinical Practice:
If this assertion is correct, bias may be prevented in future studies by categorizing injuries into volume or pacing injuries. However, more work is needed to provide further evidence in support of this approach. Future investigations of the link between training patterns and injury development should be designed as large‐scale prospective studies using objective methods to quantify training patterns.
Level of evidence:
5
PMCID: PMC3625796  PMID: 23593555
Etiology; running pace; running‐related injury; training volume
20.  Foot posture as a risk factor for lower limb overuse injury: a systematic review and meta-analysis 
Background
Static measures of foot posture are regularly used as part of a clinical examination to determine the need for foot level interventions. This is based on the premise that pronated and supinated foot postures may be risk factors for or associated with lower limb injury. This systematic review and meta-analysis investigates foot posture (measured statically) as a potential risk factor for lower limb overuse injuries.
Methods
A systematic search was performed using Medline, CINAHL, Embase, SportDiscus in April 2014, to identify prospective cohort studies that investigated foot posture and function as a risk factor for lower limb overuse injury. Eligible studies were classified based on the method of foot assessment: (i) static foot posture assessment; and/or (ii) dynamic foot function assessment. This review presents studies evaluating static foot posture. The methodological quality of included studies was evaluated by two independent reviewers, using an adapted version of the Epidemiological Appraisal Instrument (EAI). Where possible, effects were expressed as standardised mean differences (SMD) for continuous scaled data, and risk ratios (RR) for nominal scaled data. Meta-analysis was performed where injuries and outcomes were considered homogenous.
Results
Twenty-one studies were included (total n = 6,228; EAI 0.8 to 1.7 out of 2.0). There was strong evidence that a pronated foot posture was a risk factor for medial tibial stress syndrome (MTSS) development and very limited evidence that a pronated foot posture was a risk factor for patellofemoral pain development, although associated effect sizes were small (0.28 to 0.33). No relationship was identified between a pronated foot posture and any other evaluated pathology (i.e. foot/ankle injury, bone stress reactions and non-specific lower limb overuse injury).
Conclusion
This systematic review identified strong and very limited evidence of small effect that a pronated foot posture is a risk factor for MTSS and patellofemoral pain respectively. Evaluation of static foot posture should be included in a multifactorial assessment for both MTSS and patellofemoral pain, although only as a part of the potential injury risk profile. Whilst the included measures are clinically applicable, further studies are required to determine their relationship with dynamic foot function.
Electronic supplementary material
The online version of this article (doi:10.1186/s13047-014-0055-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13047-014-0055-4
PMCID: PMC4282737  PMID: 25558288
Lower extremity; Foot; Pronation; Supination; Prospective studies; Risk factors; Musculoskeletal diseases; Review
21.  RUNNING MORE THAN THREE KILOMETERS DURING THE FIRST WEEK OF A RUNNING REGIMEN MAY BE ASSOCIATED WITH INCREASED RISK OF INJURY IN OBESE NOVICE RUNNERS 
ABSTRACT
Background:
Training guidelines for novice runners are needed to reduce the risk of injury. The purpose of this study was to investigate whether the risk of injury varied in obese and non‐obese individuals initiating a running program at different weekly distances.
Methods:
A volunteer sample of 749 of 1532 eligible healthy novice runners was included in a 3‐week observational explorative prospective cohort study. Runners were categorized into one of six strata based on their body mass index (BMI) (≤30=low; >30=high) and running distance after 1 week (<3 km = low; 3 to 6 km = medium; >6 km = high). Data was collected for three weeks for the six strata. The main outcome measure was running‐related injury.
Results:
Fifty‐six runners sustained a running‐related injury during the 3‐week data collection. A significantly greater number of individuals with BMI>30 sustained injuries if they ran between 3 to 6 km (cumulative risk difference (CRD) = 14.3% [95%CI: 3.3% to 25.3%], p<0.01) or more than 6 km (CRD = 16.2% [95%CI: 4.4% to 28.0%], p<0.01) the first week than individuals in the reference group (low distance and low BMI). The effect‐measure modification between high running distance and BMI on additive scale was positive (11.7% [‐3.6% to 27.0%], p=0.13). The number of obese individuals needed to change their running distance from high to low to avoid one injury was 8.5 [95%CI: 4.6 to 52].
Conclusions:
Obese individuals were at greater risk of injury if they exceeded 3 km during the first week of their running program. Because of a considerable injury risk compared with their non‐obese peers, individuals with a BMI>30 may be well advised to begin running training with an initial running distance of less than 3 km (1.9 miles) the first week of their running regime. Large‐scale trials are needed to further describe and document this relationship.
Level of Evidence:
Level 2b
PMCID: PMC4060311  PMID: 24944852
Body mass index; distance; injury risk; Running
22.  QSRR Models for Kováts’ Retention Indices of a Variety of Volatile Organic Compounds on Polar and Apolar GC Stationary Phases Using Molecular Connectivity Indexes 
Chromatographia  2010;72(9-10):893-903.
Quantitative structure-retention relationship (QSRR) approaches, based on molecular connectivity indices are useful to predict the gas chromatography of Kováts relative retention indices (GC-RRIs) of 132 volatile organic compounds (VOCs) on different 12 (4 apolar and 8 polar) stationary phases (C67, C103, C78, C∞, POH, TTF, MTF, PCL, PBR, TMO, PSH and PCN) at 130 °C. Full geometry optimization based on Austin model 1 semi-empirical molecular orbital method was carried out. The sets of 30 molecular descriptors were derived directly from the topological structures of the compounds from DRAGON program. By means of the final variable selection method, which is elimination selection stepwise regression algorithms, three optimal descriptors were selected to develop a QSRR model to predict the RRI of organic compounds on each stationary phase with a correlation coefficient between 0.9378 and 0.9673 and a leave-one-out cross-validation correlation coefficient between 0.9325 and 0.9653. The root mean squares errors over different 12 phases were within the range of 0.0333–0.0458. Furthermore, the accuracy of all developed models was confirmed using procedures of Y-randomization, external validation through an odd–even number and division of the entire dataset into training and test sets. A successful interpretation of the complex relationship between GC RRIs of VOCs and the chemical structures was achieved by QSRR. The three connectivity indexes in the models are also rationally interpreted, which indicated that all organic compounds’ RRI was precisely represented by molecular connectivity indexes.
Electronic supplementary material
The online version of this article (doi:10.1365/s10337-010-1741-4) contains supplementary material, which is available to authorized users.
doi:10.1365/s10337-010-1741-4
PMCID: PMC2965364  PMID: 21088689
Gas chromatography; Quantitative structure–retention relationship; Kováts retention indices; Connectivity indices; Elimination selection stepwise regression algorithms
23.  Reliability and Validity of Physiological Data Obtained Within a Cycle-Run Transition Test in Age-Group Triathletes 
This study examined the validity and reliability of a sequential “Run-Bike-Run” test (RBR) in age-group triathletes. Eight Olympic distance (OD) specialists (age 30.0 ± 2.0 years, mass 75.6 ± 1.6 kg, run VO2max 63.8 ± 1.9 ml· kg-1· min-1, cycle VO2peak 56.7 ± 5.1 ml· kg-1· min-1) performed four trials over 10 days. Trial 1 (TRVO2max) was an incremental treadmill running test. Trials 2 and 3 (RBR1 and RBR2) involved: 1) a 7-min run at 15 km· h-1 (R1) plus a 1-min transition to 2) cycling to fatigue (2 W· kg-1 body mass then 30 W each 3 min); 3) 10-min cycling at 3 W· kg-1 (Bsubmax); another 1-min transition and 4) a second 7-min run at 15 km· h-1 (R2). Trial 4 (TT) was a 30-min cycle - 20-min run time trial. No significant differences in absolute oxygen uptake (VO2), heart rate (HR), or blood lactate concentration ([BLA]) were evidenced between RBR1 and RBR2. For all measured physiological variables, the limits of agreement were similar, and the mean differences were physiologically unimportant, between trials. Low levels of test-retest error (i.e. ICC <0.8, CV<10%) were observed for most (logged) measurements. However [BLA] post R1 (ICC 0.87, CV 25.1%), [BLA] post Bsubmax (ICC 0.99, CV 16.31) and [BLA] post R2 (ICC 0.51, CV 22.9%) were least reliable. These error ranges may help coaches detect real changes in training status over time. Moreover, RBR test variables can be used to predict discipline specific and overall TT performance. Cycle VO2peak, cycle peak power output, and the change between R1 and R2 (deltaR1R2) in [BLA] were most highly related to overall TT distance (r = 0.89, p < 0. 01; r = 0.94, p < 0.02; r = 0.86, p < 0.05, respectively). The percentage of TR VO2max at 15 km· h-1, and deltaR1R2 HR, were also related to run TT distance (r = -0.83 and 0.86, both p < 0.05).
Key points
It is extremely important to ensure that the measurements made as part of research or athlete support work are adequately reliable and valid.
The modified Millet triathlete “Run-Bike-Run” (RBR) test allows both for important physiological variables that are normally obtained from isolated tests (such as cycle VO2peak and peak power output) to be determined, and for measurement of the extent to which an athlete adapts to a cycle-run transition (T2).
The data reported in this paper regarding the test-retest reliability of the modified RBR, and its validity relative to cycle-run time-trial performance in male age-group triathletes, may help coaches determine the extent to which changes on test measures are likely due to training adaptation rather than to measurement error.
PMCID: PMC3763322  PMID: 24150086
Multi-discipline; reproducibility; time-trial, test, adaptation
24.  Military Exercises, Knee and Ankle Joint Position Sense, and Injury in Male Conscripts: A Pilot Study 
Journal of Athletic Training  2013;48(6):790-796.
Context:
The high incidence of lower limb injuries associated with physical exercises in military conscripts suggests that fatigue may be a risk factor for injuries. Researchers have hypothesized that lower limb injuries may be related to altered ankle and knee joint position sense (JPS) due to fatigue.
Objective:
To evaluate if military exercises could alter JPS and to examine the possible relation of JPS to future lower extremity injuries in military service.
Design:
Cohort study.
Setting:
Laboratory.
Patients or Other Participants:
A total of 50 male conscripts (age = 21.4 ± 2.3 years, height = 174.5 ± 6.4 cm, mass = 73.1 ± 6.3 kg) from a unique military base were recruited randomly.
Main Outcome Measure(s):
Participants performed 8 weeks of physical activities at the beginning of a military course. In the first part of the study, we instructed participants to recognize predetermined positions before and after military exercises so we could examine the effects of military exercise on JPS. The averages of the absolute error and the variable error of 3 trials were recorded. We collected data on the frequency of lower extremity injuries over 8 weeks. Next, the participants were divided into 2 groups: injured and uninjured. Separate 2 × 2 × 2 (group-by-time-by-joint) mixed-model analyses of variance were used to determine main effects and interactions of these factors for each JPS measure. In the second part of the study, we examined whether the effects of fatigue on JPS were related to the development of injury during an 8-week training program. We calculated Hedges effect sizes for JPS changes postexercise in each group and compared change scores between groups.
Results:
We found group-by-time interactions for all JPS variables (F range = 2.86–4.05, P < .01). All participants showed increases in JPS errors postexercise (P < .01), but the injured group had greater changes for all the variables (P < .01).
Conclusions:
Military conscripts who sustained lower extremity injuries during an 8-week military exercise program had greater loss of JPS acuity than conscripts who did not sustain injuries. The changes in JPS found after 1 bout of exercise may have predictive ability for future musculoskeletal injuries.
doi:10.4085/1062-6050-48.3.06
PMCID: PMC3867090  PMID: 23914913
fatigue; proprioception; lower extremity; muscles
25.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525

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