[Show abstract][Hide abstract] ABSTRACT: An association between higher bone mineral density (BMD) and the diagnosis of breast cancer (BC) has been reported. Data on the risk of osteoporotic fractures in women with BC are conflicting.Aims:The objective of this study was to assess fracture risk adjusted for BMD in women with and without BC, and to assess whether fracture risk in BC patients is attributed to BMD or BC characteristics.Methods:Using electronic medical records of patients who underwent dual energy X-ray absorptiometry BMD studies at Soroka University Medical Center between February 2003 and March 2011, we identified women with subsequent diagnosis of osteoporotic fractures. BC status, demographic, health characteristics, BMD, and other laboratory findings were assessed. In BC patients data on grade, stage, and treatment were collected. Primary outcome was osteoporotic fracture, analyzed by Cox proportional hazards regression models.Results:During a median follow-up of 4.9 years in 17,110 women with BMD testing (658 BC patients), 1,193 women experienced an osteoporotic fracture (62 in BC and 1,131 in no-BC groups). In multivariate analysis adjusted for age, body mass index (BMI) and BMD, hazard ratio (HR) for any osteoporotic fracture in women with BC was 1.34 (P=0.026). BMD was similar among women with and without BC who fractured. BC patients who experienced an osteoporotic fracture had a trend for less-advanced BC, lower rates of chemotherapy treatment, and higher rates of tamoxifen treatment.Conclusions:BC survivors are at increased risk of an osteoporotic fracture, which is not explained by worse BMD. Chemotherapy or aromatase inhibitors did not contribute substantially to fracture risk among our BC survivors.
[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: The objective was to evaluate compliance with osteoporosis (OP) treatments and determine the fracture and healthcare burden associated with noncompliance. Methods: This retrospective analysis of a US claims database identified women initiating an OP medication from January 1, 2002-June 30, 2009. Patients were ≥55 years and had ≥1 pharmacy claim for a bisphosphonate or non-bisphosphonate (raloxifene, calcitonin, teriparatide); the index date was the first pharmacy claim. There were three study periods: baseline (12 months pre-index); compliance period (0-12 months post-index); and follow-up period (12-24 months post-index). Medication possession ratio (MPR) was calculated during the compliance period to differentiate two cohorts: compliant (MPR ≥80%) and noncompliant (MPR <80%). Outcomes during follow-up were modeled by logistic regression (presence of fracture ), Poisson regression (healthcare utilization incidence rate) and gamma regression (healthcare costs), all adjusted for patient demographic and clinical characteristics. Results: Overall, 685,505 women initiating OP therapy were identified and 57,913 (8.4%) met the inclusion criteria: only 23,430 (40.5%) were compliant and 34,483 (59.5%) were noncompliant. Mean age was 64 years. Noncompliance was associated with a 20% higher risk of any fracture (odds ratio: 1.20, 95% CI=1.07-1.35), a higher incidence rate ratio (IRR) for inpatient utilization (IRR: 1.26, 95% CI=1.19-1.34) and a lower rate of outpatient utilization (IRR: 0.97, 95% CI=0.95-0.98). Noncompliant patients had 13% higher medical costs (cost ratio: 1.13, 95% CI=1.06-1.21) than compliant patients. Limitations: Inclusion in this study required 36 months of continuous healthcare coverage. Thus, the results are primarily applicable to a stable, managed care population and may not be generalizable to other populations. Conclusion: Noncompliance with OP therapy was associated with a higher risk of fracture, higher all-cause medical costs and a higher frequency of inpatient service utilization. Additional research is needed to identify barriers to compliance with OP therapy.
Current Medical Research and Opinion 02/2015; 31(4):1-29. DOI:10.1185/03007995.2015.1016605 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context. Several fracture prediction models that combine fractures at different sites into a composite outcome are in current use. However, to the extent individual fracture sites have differing risk factor profiles, model discrimination is impaired. Objective. To improve model discrimination by developing a 5-yr composite fracture prediction model for fracture sites that display similar risk profiles. Design. Prospective, observational cohort study. Setting. Primary care practices in 10 countries. Patients. Women aged ≥55 years. Intervention. Self-administered questionnaires collected data on patient characteristics, fracture risk factors and previous fractures. Main Outcome Measure. Main outcome is time to first clinical fracture of hip, pelvis, upper leg, clavicle, or spine, each of which exhibits a strong association with advanced age. Results. Of four composite fracture models considered, model discrimination (c index) is highest for an age-related fracture model (c index 0.75, 47,066 women), and lowest for FRAX major fracture and a 10-site model (c indices 0.67 and 0.65). The unadjusted increase in fracture risk for an additional 10 yr of age ranges from 80% to 180% for the individual bones in the age-associated model. Five other fracture sites not considered for the age-associated model (upper arm/shoulder, rib, wrist, lower leg, and ankle) have age associations for an additional 10 yr of age from a 10% decrease to a 60% increase. Conclusions. After examining results for 10 different bone fracture sites, advanced age appeared the single best possibility for uniting several different sites, resulting in an empirically based composite fracture risk model.
The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133468. DOI:10.1210/jc.2013-3468 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone. Participants: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. Conclusions: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.
[Show abstract][Hide abstract] ABSTRACT: Paget’s disease of bone (PDB) is transmitted, in one-third of cases, in an autosomal dominant mode of inheritance with incomplete penetrance. The SQSTM1/P392L germinal mutation is the most common mutation associated with PDB. Given the focal nature of PDB, one team of investigators showed that SQSTM1/P392L somatic mutations could occur in pagetic bone lesions in the absence of germinal mutations detectable in the peripheral blood. The objectives of this study were to develop a reliable method to detect SQSTM1/P392L post-zygotic mutations, by optimizing a polymerase chain reaction (PCR)-clamping method reported to be effective in detecting post-zygotic mutations in peripheral blood from patients with fibrous dysplasia; and to evaluate the frequency of this post-zygotic mutation in PDB patients. We used a locked nucleic acid (LNA) specifically designed for the SQSTM1/P392L mutation, which blocks the wild-type allele amplification during the PCR. DNA from 376 pagetic patients and 297 controls, all without any SQSTM1/P392L germinal mutation, was analyzed. We found that 4.8 % of PDB patients and 1.4 % of controls were carriers of this post-zygotic mutation [p = 0.013, OR 3.68 (1.23; 11.00)]. PDB patient carriers of a post-zygotic mutation had a lower number of affected bones and Renier’s index than patients carrying a germinal mutation, suggesting a lower disease extension. We also demonstrated that this post-zygotic mutation was restricted to the monocytic lineage. These results confirmed that LNA PCR clamping is effective for the detection of SQSTM1/P392L post-zygotic mutations, which may occur in patients with PDB.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-014-1488-3) contains supplementary material, which is available to authorized users.
Human Genetics 09/2014; 134(1). DOI:10.1007/s00439-014-1488-3 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine persistence with subcutaneous denosumab every 6 months in women being treated for osteoporosis, we conducted a single-arm prospective, observational study in the United States and Canada. Among 935 patients enrolled, 12-month persistence was 82 %, with 66 patients (7 %) reporting serious adverse events and 19 patients (2 %) reporting fractures.
Increased persistence with osteoporosis therapy is associated with reduced fracture risk. Denosumab reduced fracture risk in clinical trials; persistence in community settings is undetermined. This study evaluates persistence with denosumab in community practice in the United States (US) and Canada.
In a 24-month multicenter, prospective, single-arm, observational study, women being treated for osteoporosis were enrolled ≤4 weeks after the first subcutaneous injection of denosumab. For this 12-month prespecified interim analysis, endpoints include persistence (one injection at study entry and another within 6 months + 8 weeks), attributes associated with persistence (univariate analysis), and serious adverse events (SAEs).
Among 935 patients (mean age 71 years), mean baseline T-scores were −2.18 (femoral neck) and −2.00 (lumbar spine); 50 % of patients had experienced osteoporotic fracture(s). At 12 months, 82 % of patients were persistent with denosumab. Baseline factors significantly (p 5 years previously, lumbar spine T-score > −2.5, and treatment by female physicians (US). Lower persistence was associated (p
Osteoporosis International 09/2014; 26(1). DOI:10.1007/s00198-014-2871-6 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis and diabetes mellitus are chronic diseases with significant associated morbidity and mortality. Recent evidence suggests that both type 1 and type 2 diabetes are associated with an increased fracture risk. Fracture as a complication of diabetes must be considered when evaluating and treating patients with diabetes.
Endocrinology and metabolism clinics of North America 03/2014; 43(1):233-243. DOI:10.1016/j.ecl.2013.09.004 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis causes an elevated fracture risk. We propose the continued use of T-scores as one means for diagnosis but recommend that, alternatively, hip fracture; osteopenia-associated vertebral, proximal humerus, pelvis, or some wrist fractures; or FRAX scores with ≥3 % (hip) or 20 % (major) 10-year fracture risk also confer an osteoporosis diagnosis.
Osteoporosis is a common disorder of reduced bone strength that predisposes to an increased risk for fractures in older individuals. In the USA, the standard criterion for the diagnosis of osteoporosis in postmenopausal women and older men is a T-score of ≤ -2.5 at the lumbar spine, femur neck, or total hip by bone mineral density testing.
Under the direction of the National Bone Health Alliance, 17 clinicians and clinical scientists were appointed to a working group charged to determine the appropriate expansion of the criteria by which osteoporosis can be diagnosed.
The group recommends that postmenopausal women and men aged 50 years should be diagnosed with osteoporosis if they have a demonstrable elevated risk for future fractures. This includes having a T-score of less than or equal to -2.5 at the spine or hip as one method for diagnosis but also permits a diagnosis for individuals in this population who have experienced a hip fracture with or without bone mineral density (BMD) testing and for those who have osteopenia by BMD who sustain a vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fracture. Finally, the term osteoporosis should be used to diagnose individuals with an elevated fracture risk based on the World Health Organization Fracture Risk Algorithm, FRAX.
As new ICD-10 codes become available, it is our hope that this new understanding of what osteoporosis represents will allow for an appropriate diagnosis when older individuals are recognized as being at an elevated risk for fracture.
Osteoporosis International 02/2014; 25(5). DOI:10.1007/s00198-014-2655-z · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p < 0.001). For ankle fractures, linear weight showed a significant positive association: adjusted HR per 5-kg increase 1.05 (1.02-1.07) (p < 0.001). For upper arm/shoulder and clavicle fractures, only linear height was significantly associated: adjusted HRs per 10-cm increase were 0.85 (0.75-0.97) (p = 0.02) and 0.73 (0.57-0.92) (p = 0.009), respectively. For pelvic and rib fractures, the best models were for nonlinear BMI or weight (p = 0.05 and 0.03, respectively), with inverse associations at low BMI/body weight and positive associations at high values. These data demonstrate that the relationships between fracture and weight, BMI, and height are site-specific. The different associations may be mediated, at least in part, by effects on bone mineral density, bone structure and geometry, and patterns of falling.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2014; 29(2). DOI:10.1002/jbmr.2051 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anti-osteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining ≥2 fractures while on AOM. GLOW is a prospective, observational cohort study of women aged ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey-years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow-up, 73/5550 women in the AOM group (1.3%) and 123/21,368 in the non-AOM group (0.6%) reported occurrence of ≥2 fractures. The following variables were associated with treatment failure: lower SF-36 score (physical function and vitality) at baseline, higher FRAX score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss ≥10 lb (≥4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF-36 vitality score (odds ratio [OR] per 10-point increase 0.85; 95% confidence interval [CI] 0.76-0.95; p = 0.004), ≥2 falls in the past year (OR 2.40; 95% CI 1.34-4.29; p = 0.011), and prior fracture (OR 2.93; 95% CI 1.81-4.75; p < 0.0001). The C statistic for the model was 0.712. Specific strategies for fracture prevention should therefore be developed for this subgroup of patients.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2014; 29(1). DOI:10.1002/jbmr.2023 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine when, where and how fractures occur in postmenopausal women.
We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3.
Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68-86% of NHNV and 68-83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling.
In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year.
PLoS ONE 12/2013; 8(12):e83306. DOI:10.1371/journal.pone.0083306 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Background: Multiple therapies are approved for the treatment of osteoporosis (OP), but many patients with osteoporosis may not initiate treatment upon osteoporosis diagnosis. Objective: To characterize initiation of pharmacologic OP treatment among women within 1 year of OP diagnosis in a US managed care population. Research design and methods: The retrospective cohort study included women aged ≥ 55 years with a claims-documented diagnosis of OP who were naïve to OP medications prior to OP diagnosis (index date) during 2001-2010. Continuous enrollment for 12 months before (baseline) and after (follow-up) the index date was required. Patients who received OP medications but did not have an OP diagnosis were excluded. Differences in baseline characteristics between the treated and untreated cohorts were compared using Wilcoxon rank-sum (continuous variables) and chi-square tests (categorical variables). Main outcomes measures: During the follow-up period, the percentages of patients treated with bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid) and non-bisphosphonates (calcitonin, raloxifene, teriparatide) were determined. Results: A total of 65,344 patients, mean age 65.7 years, met study inclusion exclusion criteria. During the follow-up period, 42,033 patients (64.3%) received no OP medication and 23,311 patients (35.7%) received OP treatment. A total of 20,200 patients (30.9% of total study population) received bisphosphonates and 3,111 (4.8% of total) patients received non-bisphosphonates as their index medication. At baseline, untreated patients were slightly older and had higher rates of hypertension, chronic inflammatory joint disease, diabetes mellitus, and gastrointestinal events (P≤0.01) compared with treated patients. Conclusions: Among women aged ≥55 years in a US managed care population, 64.3% received no pharmacologic treatment within 1 year after being diagnosed with OP. We were not able to determine if untreated patients did not receive or did not fill a prescription. Further research is needed to understand the barriers to OP treatment and reasons for non-treatment.
Current Medical Research and Opinion 10/2013; 30(1). DOI:10.1185/03007995.2013.851074 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.
Calcified Tissue International 09/2013; 94(2). DOI:10.1007/s00223-013-9801-z · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested an inverse relationship between bone mineral density (BMD) and breast cancer incidence. The primary objective of this study was to assess whether BMD is associated with risk of subsequent breast cancer occurrence in the female population of southern Israel.
The electronic medical charts of women who underwent BMD at the Soroka Medical Center (SMC) between February 2003 and March 2011 were screened for subsequent breast cancer diagnoses. Women were divided by tertiles of BMD at 3 skeletal sites: lumbar spine (LS, L1-4), total hip (TH) and femoral neck (FN). The incidence of breast cancer was calculated.
Of 15268 women who underwent BMD testing, 86 were subsequently diagnosed with breast cancer. Most women in the study were older than 50 years (94.2% and 92.7%, respectively; p = 0.597). Women who subsequently developed breast cancer had a higher mean body-mass index (BMI) (30.9±5.5 vs. 29.1±5.7 p = 0.004) and the mean BMD Z-score was significantly higher than in those without breast cancer for all 3 skeletal sites (LS: 0.36±1.58 vs. -0.12±1.42, p = 0.002; TH: 0.37±1.08 vs. 0.03±1.02, p = 0.002; FN: 0.04±0.99 vs. -0.18±0.94; p = 0.026). Women in the highest Z-score tertiles at the FN and TH had a higher chance of developing breast cancer compared to the lowest tertile; odds ratio of 2.15, 2.02, respectively (P = 0.004 and 0.01 respectively). No association was found between the BMD Z-score and the stage, histology, grade or survival from breast cancer.
This study provides additional support for an inverse association between BMD and the risk of breast cancer.
PLoS ONE 09/2013; 8(8):e70980. DOI:10.1371/journal.pone.0070980 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles.
INTRODUCTION: We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW).
METHODS: GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged >/=55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures.
RESULTS: In total 2,945/43,832 (6.8 %) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95 % confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46 %) or lower than (36 %) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29 % experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities.
CONCLUSIONS: Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.
Osteoporosis International 07/2013; 25(1). DOI:10.1007/s00198-013-2438-y · 4.17 Impact Factor