Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial.

INTRODUCTION: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A. AIM: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A. METHODS: Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs. RESULTS: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44). CONCLUSIONS: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population.

Long-term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: Final results from the guardian 2 extension trial.

INTRODUCTION: Turoctocog alfa is a recombinant factor VIII (FVIII) molecule, approved for treatment and prophylaxis of bleeding in patients with haemophilia A. In the guardian 1 (adolescents/adults) and guardian 3 (children) phase 3 trials, turoctocog alfa demonstrated a favourable efficacy and safety profile. Guardian 1 or 3 completers could enrol in the guardian 2 extension. Final guardian 2 results are reported here. AIM: Investigate long-term safety and efficacy of turoctocog alfa administered for prophylaxis and treatment of bleeds. METHODS: In this phase 3b open-label trial, previously treated males of all ages with severe haemophilia A received prophylaxis regimens of turoctocog alfa or on-demand treatment of bleeds. The primary safety endpoint was frequency of FVIII inhibitor development. Efficacy endpoints included annualized bleeding rate (ABR) during prophylaxis, haemostatic response in treatment of bleeds and number of injections required to treat bleeds. RESULTS: Overall, 213 patients were dosed with turoctocog alfa; 207 patients received prophylaxis; 19 received on-demand treatment. No FVIII inhibitors (≥0.6 BU) were reported. For all patients on prophylaxis, overall median ABR was 1.37 bleeds/y; success rate for treatment of bleeds was 90.2%; and 88.2% of bleeds were controlled with 1-2 injections of turoctocog alfa. For the on-demand regimen, overall median ABR was 30.44 bleeds/y; success rate for treatment of bleeds was 96.7%; and 94.9% of bleeds were controlled with 1-2 injections of turoctocog alfa. CONCLUSION: Extended use of turoctocog alfa is safe and effective for prevention and treatment of bleeding episodes in previously treated patients with haemophilia A across all ages.

Individual courses of low back pain in adult Danes: a cohort study with 4-year and 8-year follow-up.

BACKGROUND: Few longitudinal studies have described the variation in LBP and its impact over time at an individual level. The aims of this study were to: 1) determine the prevalence of LBP in three surveys over a 9-year period in the Danish general population, using five different definitions of LBP, 2) study their individual long-term courses, and 3) determine the odds of reporting subsequent LBP when having reported previous LBP. METHODS: A cohort of 625 men and women aged 40 was sampled from the general population. Questions about LBP were asked at ages 41, 45 and 49, enabling individual courses to be tracked across five different definitions of LBP. Results were reported as percentages and the prognostic influence on future LBP was reported as odds ratios (OR). RESULTS: Questionnaires were completed by 412 (66%), 348 (56%) and 293 (47%) persons respectively at each survey. Of these, 293 (47%) completed all three surveys. The prevalence of LBP did not change significantly over time for any LBP past year: 69, 68, 70%; any LBP past month: 42, 48, 41%; >30 days LBP past year: 25, 27, 24%; seeking care for LBP past year: 28, 30, 36%; and non-trivial LBP, i.e. LBP >30 days past year including consequences: 18, 20, 20%. For LBP past year, 2/3 remained in this category, whereas four out of ten remained over the three time-points for the other definitions of LBP. Reporting LBP defined in any of these ways significantly increased the odds for the same type of LBP 4 years later. For those with the same definition of LBP at both 41 and 45 years, the risk of also reporting the same at 49 years was even higher, regardless of definition, and most strongly for seeking care and non-trivial LBP (OR 17.6 and 18.4) but less than 11% were in these groups. CONCLUSION: The prevalence rates of LBP, when defined in a number of ways, were constant over time at a group level, but did not necessarily involve the same individuals. Reporting more severe LBP indicated a higher risk of also reporting future LBP but less than 11% were in these categories at each survey.

Reduced risk of hypoglycemia with insulin degludec versus insulin glargine in patients with type 2 diabetes requiring high doses of basal insulin: a meta-analysis of 5 randomized begin trials.

OBJECTIVE: This meta-analysis of 5 trials from the Phase 3a insulin degludec (IDeg) clinical trial program evaluated the risk of hypoglycemia in a subset of subjects with type 2 diabetes (T2D) who required high basal insulin doses at the end of the trials. METHODS: This meta-analysis compared glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), basal insulin dose, body weight, and rates of overall and nocturnal confirmed hypoglycemia in a pooled population of T2D subjects using >60 U basal insulin at trial completion. Five Phase 3a, open-label, randomized, treat-to-target, confirmatory 26- or 52-week trials with IDeg (n = 2,262) versus insulin glargine (IGlar) (n = 1,110) administered once daily were included. Overall confirmed hypoglycemia was defined as self-measured blood glucose >56 mg/dL or any episode requiring assistance; nocturnal confirmed hypoglycemia had an onset between 00:01 and 05:59 AM. RESULTS: More than one-third of IDeg- (35%) and IGlar- (34%) treated T2D subjects required >60 U of basal insulin daily at the ends of the trial. Patients achieved similar mean HbA1c values (estimated treatment difference [ETD] IDeg - IGlar: 0.05%, P = .44) while mean FPG values were lower with IDeg than IGlar (ETD: -5.9 mg/dL, P = .04) at end-of-trial. There was a 21% lower rate of overall confirmed hypoglycemic episodes for IDeg (estimated rate ratio [RR] IDeg/IGlar: 0.79, P = .02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes for IDeg (RR: 0.48, P<.01). CONCLUSION: In this post hoc meta-analysis, more than 30% of subjects with T2D required >60 U/day of basal insulin at the end of the trials. In these individuals, IDeg achieves similar HbA1c reduction with significantly less overall and nocturnal confirmed hypoglycemia compared with IGlar.

Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage.

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03-0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06-5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03-1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

Medical school dropout--testing at admission versus selection by highest grades as predictors.

CONTEXT: Very few studies have reported on the effect of admission tests on medical school dropout. The main aim of this study was to evaluate the predictive validity of non-grade-based admission testing versus grade-based admission relative to subsequent dropout. METHODS: This prospective cohort study followed six cohorts of medical students admitted to the medical school at the University of Southern Denmark during 2002-2007 (n=1544). Half of the students were admitted based on their prior achievement of highest grades (Strategy 1) and the other half took a composite non-grade-based admission test (Strategy 2). Educational as well as social predictor variables (doctor-parent, origin, parenthood, parents living together, parent on benefit, university-educated parents) were also examined. The outcome of interest was students' dropout status at 2 years after admission. Multivariate logistic regression analysis was used to model dropout. RESULTS: Strategy 2 (admission test) students had a lower relative risk for dropping out of medical school within 2 years of admission (odds ratio 0.56, 95% confidence interval 0.39-0.80). Only the admission strategy, the type of qualifying examination and the priority given to the programme on the national application forms contributed significantly to the dropout model. Social variables did not predict dropout and neither did Strategy 2 admission test scores. CONCLUSIONS: Selection by admission testing appeared to have an independent, protective effect on dropout in this setting.

Prevalence and tracking of back pain from childhood to adolescence.

BACKGROUND: It is generally acknowledged that back pain (BP) is a common condition already in childhood. However, the development until early adulthood is not well understood and, in particular, not the individual tracking pattern. The objectives of this paper are to show the prevalence estimates of BP, low back pain (LBP), mid back pain (MBP), neck pain (NP), and care-seeking because of BP at three different ages (9, 13 and 15 years) and how the BP reporting tracks over these age groups over three consecutive surveys. METHODS: A longitudinal cohort study was carried out from the years of 1997 till 2005, collecting interview data from children who were sampled to be representative of Danish schoolchildren. BP was defined overall and specifically in the three spinal regions as having reported pain within the past month. The prevalence estimates and the various patterns of BP reporting over time are presented as percentages. RESULTS: Of the 771 children sampled, 62%, 57%, and 58% participated in the three back surveys and 34% participated in all three. The prevalence estimates for children at the ages of 9, 13, and 15, respectively, were for BP 33%, 28%, and 48%; for LBP 4%, 22%, and 36%; for MBP 20%, 13%, and 35%; and for NP 10%, 7%, and 15%. Seeking care for BP increased from 6% and 8% at the two youngest ages to 34% at the oldest. Only 7% of the children who participated in all three surveys reported BP each time and 30% of these always reported no pain. The patterns of development differed for the three spinal regions and between genders. Status at the previous survey predicted status at the next survey, so that those who had pain before were more likely to report pain again and vice versa. This was most pronounced for care-seeking. CONCLUSION: It was confirmed that BP starts early in life, but the patterns of onset and development over time vary for different parts of the spine and between genders. Because of these differences, it is recommended to report on BP in youngsters separately for the three spinal regions, and to differentiate in the analyses between the genders and age groups. Although only a small minority reported BP at two or all three surveys, tracking of BP (particularly NP) and care seeking was noted from one survey to the other. On the positive side, individuals without BP at a previous survey were likely to remain pain free at the subsequent survey.

Illustrative Cases from the Pathfinder Clinical Trials of Patients with Hemophilia A Treated with Turoctocog Alfa Pegol (N8-GP).

PURPOSE: To illustrate the benefits of the extended half-life (EHL) recombinant factor VIII product N8-GP (Esperoct®, turoctocog alfa pegol) by describing individual cases of patients with severe hemophilia A treated with N8-GP in the pathfinder clinical trial program. PATIENTS AND METHODS: This manuscript presents selected patient cases from the pivotal pathfinder clinical trial program, which included a number of clinical studies in adults (pathfinder 2 and 3) and children (pathfinder 5); overall results published previously. Clinical data and outcomes described in this manuscript are more detailed and derived from several interesting patient cases (five adults from pathfinder 2 and two children from pathfinder 5), who received N8-GP as prophylaxis (PPX) for their severe hemophilia A. Three of the five adults described here also underwent multiple major surgeries (for which they moved from pathfinder 2 into pathfinder 3 and later returned to pathfinder 2). New analyses on pediatric joint health from pathfinder 5 are also summarized here. Outcomes assessed included bleeding complications, improvements in quality of life, intraoperative hemostatic response, blood loss during surgery, number of blood transfusions, and annualized bleeding rates. For the pediatric patients, target joint resolution, adverse events, and annualized joint bleeding rate were also assessed, all by the treating physician. RESULTS: Considerable improvements in treatment adherence, bleeding rates, and overall physical activity levels were demonstrated in two adult cases from the pathfinder 2 trial. N8-GP demonstrated good or excellent hemostatic coverage in three adult patients undergoing multiple major surgeries. The benefits of N8-GP for joint health and in support of children and adolescents with evolving active lifestyles were reported for several pediatric cases. CONCLUSION: These patient cases highlight the benefits of EHL products, such as N8-GP, for patients with severe hemophilia A. They include more challenging scenarios relating to improvements in previously poor adherence to PPX, children with active sporting lifestyles, and patients requiring multiple major surgeries.

The association between aerobic fitness and physical activity in children and adolescents: the European youth heart study.

The link between aerobic fitness and physical activity in children has been studied in a number of earlier studies and the results have generally shown weak to moderate correlations. This overall finding has been widely questioned partly because of the difficulty in obtaining valid estimates of physical activity. This study investigated the cross-sectional and longitudinal relationship between aerobic fitness and physical activity in a representative sample of 9 and 15-year-old children (n = 1260 cross-sectional, n = 153 longitudinal). The specific goal was to improve past studies using an objective method of activity assessment and taking into account a number of major sources of error. Data came from the Danish part of the European youth heart study, 1997-2003. The cross-sectional results generally showed a weak to moderate association between aerobic fitness and physical activity with standardized regression coefficients ranging from 0.14 to 0.33. The longitudinal results revealed a tendency towards an interaction effect of baseline physical activity on the relationship between changes in physical activity and aerobic fitness. Moderate to moderately strong regression effect sizes were observed in the lower quadrant of baseline physical activity compared to weak effect sizes in the remaining quadrants. In conclusion, the present study confirms earlier findings of a weak to moderate association between aerobic fitness and physical activity in total population of children. However, the study also indicates that inactive children can achieve notable increase in aerobic fitness by increasing their habitual physical activity level. A potential physiological explanation for these results is highlighted.

Predictors of new vertebral endplate signal (Modic) changes in the general population.

Vertebral endplate signal changes (VESC), also known as Modic changes, have been reported to be associated with low back pain (LBP). However, little is known about predisposing factors for the development of new VESC. The aim of this study was to investigate the predictive value of lifestyle factors and disc-related magnetic resonance imaging (MRI) findings in relation to the development of new VESC. This prospective observational study included 344 people from the Danish general population who had an MRI and completed LBP questionnaires at the age of 40 and again at 44 years. Potential predictors of new VESC were female gender, disc-related MRI findings (disc degeneration, disc bulges, disc herniation, and other endplate changes) and lifestyle factors [high physical work or leisure activity, high body mass index (BMI), and heavy smoking]. Bivariate and multivariate logistic regressions were used to identify predictors of new VESC. New VESC at the age of 44 appeared in 67 of the 344. The majority (84%) of these new signal changes were type 1 VESC and almost half (45%) were only in the endplate and did not extend into the vertebral body. In the multivariate analysis, lumbar disc levels with disc degeneration, bulges or herniations at 40 were the only predictors of new VESC at age 44. Therefore, the development of new VESC at the age of 44 appears to be based on the status and dynamics of the disc, rather than being the result of gender or lifestyle factors such as smoking and physical load.

An educational approach based on a non-injury model compared with individual symptom-based physical training in chronic LBP. A pragmatic, randomised trial with a one-year follow-up.

BACKGROUND: In the treatment of chronic back pain, cognitive methods are attracting increased attention due to evidence of effectiveness similar to that of traditional therapies. The purpose of this study was to compare the effectiveness of performing a cognitive intervention based on a non-injury model with that of a symptom-based physical training method on the outcomes of low back pain (LBP), activity limitation, LBP attitudes (fear-avoidance beliefs and back beliefs), physical activity levels, sick leave, and quality of life, in chronic LBP patients. METHODS: The study was a pragmatic, single-blind, randomised, parallel-group trial. Patients with chronic/recurrent LBP were randomised to one of the following treatments: 1. Educational programme : the emphasis was on creating confidence that the back is strong, that loads normally do not cause any damage despite occasional temporary pain, that reducing the focus on the pain might facilitate more natural and less painful movements, and that it is beneficial to stay physically active. 2. Individual symptom-based physical training programme : directional-preference exercises for those centralising their pain with repetitive movements; 'stabilising exercises' for those deemed 'unstable' based on specific tests; or intensive dynamic exercises for the remaining patients. Follow-up questionnaires (examiner-blinded) were completed at 2, 6 and 12 months. The main statistical test was an ANCOVA adjusted for baseline values. RESULTS: A total of 207 patients participated with the median age of 39 years (IQR 33-47); 52% were female, 105 were randomised to the educational programme and 102 to the physical training programme. The two groups were comparable at baseline. For the primary outcome measures, there was a non-significant trend towards activity limitation being reduced mostly in the educational programme group, although of doubtful clinical relevance. Regarding secondary outcomes, improvement in fear-avoidance beliefs was also better in the educational programme group. All other variables were about equally influenced by the two treatments. The median number of treatment sessions was 3 for the educational programme group and 6 for the physical training programme group. CONCLUSIONS: An educational approach to treatment for chronic LBP resulted in at least as good outcomes as a symptom-based physical training method, despite fewer treatment sessions.

Generalisability of a composite student selection programme.

UNLABELLED: OBJECTIVES The reliability of individual non-cognitive admission criteria in medical education is controversial. Nonetheless, non-cognitive admission criteria appear to be widely used in selection to medicine to supplement the grades of qualifying examinations. However, very few studies have examined the overall test generalisability of composites of non-cognitive admission variables in medical education. We examined the generalisability of a composite process for selection to medicine, consisting of four variables: qualifications (application form information); written motivation (in essay format); general knowledge (multiple-choice test), and a semi-structured admission interview. The aim of this study was to estimate the generalisability of a composite selection. METHODS: Data from 307 applicants who participated in the admission to medicine in 2007 were available for analysis. Each admission parameter was double-scored using two random, blinded and independent raters. Variance components for applicant, rater and residual effects were estimated for a mixed model with the restricted maximum likelihood (REML) method. The reliability of obtained applicant ranks (G coefficients) was calculated for individual admission criteria and for composite admission procedures. RESULTS: A pre-selection procedure combining qualification and motivation scores showed insufficient generalisability (G = 0.45). The written motivation in particular, displayed low generalisability (G = 0.10). Good generalisability was found for the admission interview (G = 0.86), and for the final composite selection procedure (G = 0.82). CONCLUSIONS: This study revealed good generalisability of a composite selection, but indicated that the application, composition and weighting of individual admission variables should not be random. Knowledge of variance components and generalisability of individual admission variables permits evidence-based decisions on optimal selection strategies.

What is an acceptable outcome of treatment before it begins? Methodological considerations and implications for patients with chronic low back pain.

Understanding changes in patient-reported outcomes is indispensable for interpretation of results from clinical studies. As a consequence the term "minimal clinically important difference" (MCID) was coined in the late 1980s to ease classification of patients into improved, not changed or deteriorated. Several methodological categories have been developed determining the MCID, however, all are subject to weaknesses or biases reducing the validity of the reported MCID. The objective of this study was to determine the reproducibility and validity of a novel method for estimating low back pain (LBP) patients' view of an acceptable change (MCID(pre)) before treatment begins. One-hundred and forty-seven patients with chronic LBP were recruited from an out-patient hospital back pain unit and followed over an 8-week period. Original and modified versions of the Oswestry disability index (ODI), Bournemouth questionnaire (BQ) and numeric pain rating scale (NRS(pain)) were filled in at baseline. The modified questionnaires determined what the patient considered an acceptable post-treatment outcome which allowed us to calculate the MCID(pre). Concurrent comparisons between the MCID(pre), instrument measurement error and a retrospective approach of establishing the minimal clinically important difference (MCID(post)) were made. The results showed the prospective acceptable outcome method scores to have acceptable reproducibility outside measurement error. MCID(pre) was 4.5 larger for the ODI and 1.5 times larger for BQ and NRS(pain) compared to the MCID(post). Furthermore, MCID(pre) and patients post-treatment acceptable change was almost equal for the NRS(pain) but not for the ODI and BQ. In conclusion, chronic LBP patients have a reasonably realistic idea of an acceptable change in pain, but probably an overly optimistic view of changes in functional and psychological/affective domains before treatment begins.

Characteristics and natural course of vertebral endplate signal (Modic) changes in the Danish general population.

BACKGROUND: Vertebral endplate signal changes (VESC) are more common among patients with low back pain (LBP) and/or sciatica than in people who are not seeking care for back pain. The distribution and characteristics of VESC have been described in people from clinical and non-clinical populations. However, while the clinical course of VESC has been studied in patients, the natural course in the general population has not been reported. The objectives of this prospective observational study were to describe: 1) the distribution and characteristics of VESC in the lumbar spine, 2) its association with disc degeneration, and 3) its natural course from 40 to 44 years of age. METHODS: Three-hundred-and-forty-four individuals (161 men and 183 women) sampled from the Danish general population had MRI at the age of 40 and again at the age of 44. The following MRI findings were evaluated using standardised evaluation protocols: type, location, and size of VESC, disc signal, and disc height. Characteristics and distribution of VESC were analysed by frequency tables. The association between VESC and disc degeneration was analysed by logistic regression analysis. The change in type and size of VESC was analysed by cross-tabulations of variables obtained at age 40 and 44 and tested using McNemar's test of symmetry. RESULTS: Two-thirds (67%) of VESC found in this study were located in the lower part of the spine (L4-S1). VESC located at disc levels L1-L3 were generally small and located only in the anterior part of the vertebra, whereas those located at disc levels L4-S1 were more likely to extend further into the vertebra and along the endplate. Moreover, the more the VESC extended into the vertebra, the more likely it was that the adjacent disc was degenerated. The prevalence of endplate levels with VESC increased significantly from 6% to 9% from age 40 to 44. Again, VESC that was only observed in the endplate was more likely to come and go over the four-year period compared with those which extended further into the vertebra, where it generally persisted. CONCLUSION: The prevalence of VESC increased significantly over the four-year period. Furthermore, the results from this study indicate that the distribution of VESC, its association with disc degeneration and its natural course, is dependent on the size of the signal changes.

Unit-specific calibration of Actigraph accelerometers in a mechanical setup - is it worth the effort? The effect on random output variation caused by technical inter-instrument variability in the laboratory and in the field.

BACKGROUND: Potentially, unit-specific in-vitro calibration of accelerometers could increase field data quality and study power. However, reduced inter-unit variability would only be important if random instrument variability contributes considerably to the total variation in field data. Therefore, the primary aim of this study was to calculate and apply unit-specific calibration factors in multiple accelerometers in order to examine the impact on random output variation caused by inter-instrument variability. METHODS: Instrument-specific calibration factors were estimated in 25 MTI- and 53 CSA accelerometers in a mechanical setup using four different settings varying in frequencies and/or amplitudes. Calibration effect was analysed by comparing raw and calibrated data after applying unit-specific calibration factors to data obtained during quality checks in a mechanical setup and to data collected during free living conditions. RESULTS: Calibration reduced inter-instrument variability considerably in the mechanical setup, both in the MTI instruments (raw SDbetween units = 195 counts*min-1 vs. calibrated SDbetween units = 65 counts*min-1) and in the CSA instruments (raw SDbetween units = 343 counts*min-1 vs. calibrated SDbetween units = 67 counts*min-1). However, the effect of applying the derived calibration to children's and adolescents' free living physical activity data did not alter the coefficient of variation (CV) (children: CVraw = 30.2% vs. CVcalibrated = 30.4%, adolescents: CVraw = 36.3% vs. CVcalibrated = 35.7%). High correlations (r = 0.99 & r = 0.98, respectively) were observed between raw and calibrated field data, and the proportion of the total variation caused by the MTI- and CSA monitor was estimated to be only 1.1% and 4.2%, respectively. Compared to the CSA instruments, a significantly increased (9.95%) mean acceleration response was observed post hoc in the batch of MTI instruments, in which a significantly reduced inter-instrumental reliability was observed over time. CONCLUSION: The application of unit-specific calibration factors to data collected during free living conditions had no apparent effect on inter-instrument variability. In all probability, the effect of technical calibration was primarily attenuated in the field by other more dominant sources of variation. However, routine technical assessments are still very important for determining the acceleration responses in the batch of instruments being used and, if performed after every field use, for preventing decidedly broken instruments from being returned into the field repeatedly.

Adverse pregnancy outcome in women with mild glucose intolerance: is there a clinically meaningful threshold value for glucose?

BACKGROUND: The diagnostic criteria of gestational diabetes mellitus (GDM) have been based on the risk of future maternal diabetes rather than the short-term risk of mother and infant. Our aim was to illustrate the relation between various adverse pregnancy outcomes and maternal glucose levels in women with mild glucose intolerance using a graphical approach. METHODS: Observational study of 2,885 pregnant women examined with a 2-h, 75-g oral glucose tolerance test (OGTT) based on risk indicators. Only women with 2-h capillary blood glucose <9.0 mmol/l were included, as women with 2-h values > or =9.0 mmol/l were treated for GDM. Empirical frequencies of adverse outcomes were related to 2-h values by linear and quadratic logistic models. Adjustments for well-known confounders were performed by a multiple logistic model. RESULTS: Linear trends were demonstrated for the outcomes: shoulder dystocia, caesarean section rate (univariate analysis only), spontaneous preterm delivery, and macrosomia (large-for-gestational age infants). None of the outcomes deviated significantly from linearity. No significant trend was found for hypertension or neonatal hypoglycaemia and jaundice. CONCLUSIONS: A gradually increasing risk for a number of adverse pregnancy outcomes was found with increasing glucose levels. No obvious threshold value for GDM was demonstrated for 2-h values up to 9.0 mmol/l.

Does socioeconomic status in adolescence predict low back pain in adulthood? A repeated cross-sectional study of 4,771 Danish adolescents.

Social and economic disadvantage is associated with general poor physical health. This relationship has been recognised for centuries, but it is unknown whether socioeconomic factors have a specific influence on low back pain (LBP). Furthermore, it is unknown how social and economic disadvantages in youth affect adult health. Therefore, the specific objectives of this study are to explore (1) the cross-sectional association between socioeconomic status (SES) and LBP in adolescence and (2) the longitudinal association between SES in adolescence and LBP in early adulthood. A database containing LBP data from 4,771 twins was merged with their parents' social and economic data, available from Statistics Denmark. Low back pain data ['any low back pain' and 'persistent low back pain (more than 30 days)'] were collected in 1994, when the subjects were 12-18 years of age, and collected again eight years later. Socioeconomic data of the parents (education, income, social class and long-term illness, all for both mother and father) were collected in 1994. Logistic regression analyses were used to estimate the associations between each parameter of parental SES in adolescence and LBP at baseline as well as at follow-up. Finally, the influence of a variable combining the different socioeconomic parameters was established. All estimates were controlled for smoking, alcohol consumption and body mass index at baseline. In the logistic regression models, only three of the 32 estimates were statistically significant. When merging the socioeconomic variables into a combined score, the results indicated that a good social background had a protective effect against the persistent LBP, while there was no association with any LBP. However, the statistical significance of this effect was unclear. We found no or very weak indications of possible relationships between social factors in adolescence and LBP at baseline and at follow-up.

Are MRI-defined fat infiltrations in the multifidus muscles associated with low back pain?

BACKGROUND: Because training of the lumbar muscles is a commonly recommended intervention in low back pain (LBP), it is important to clarify whether lumbar muscle atrophy is related to LBP. Fat infiltration seems to be a late stage of muscular degeneration, and can be measured in a non-invasive manner using magnetic resonance imaging. The purpose of this study was to investigate if fat infiltration in the lumbar multifidus muscles (LMM) is associated with LBP in adults and adolescents. METHODS: In total, 412 adults (40-year-olds) and 442 adolescents (13-year-olds) from the general Danish population participated in this cross-sectional cohort study. People with LBP were identified through questionnaires. Using MRI, fat infiltration of the LMM was visually graded as none, slight or severe. Odds ratios were calculated for both age groups, taking into account sex, body composition and leisure time physical activity for both groups, and physical workload (in adults only) or daily bicycling (in adolescents only). RESULTS: Fat infiltration was noted in 81% of the adults but only 14% of the adolescents. In the adults, severe fat infiltration was strongly associated with ever having had LBP (OR 9.2; 95% CI 2.0-43.2), and with having LBP in the past year (OR 4.1; 1.5-11.2), but there was no such association in adolescents. None of the investigated moderating factors had an obvious effect on the OR in the adults. CONCLUSION: Fat infiltration in the LMM is strongly associated with LBP in adults only. However, it will be necessary to quantify these measurements objectively and to investigate the direction of this link longitudinally in order to determine if the abnormal muscle is the cause of LBP or vice versa.

Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.

OBJECTIVE: To study the prevalence and importance of aspirin resistance in patients with an evolving acute myocardial infarction (AMI) by use of the Platelet Function Analyzer-100. INTRODUCTION: Previous studies have demonstrated the existence of aspirin resistance, but the clinical relevance of the phenomenon remains to be clarified. If aspirin resistant patients comprise a high-risk subgroup, it might be expected that the prevalence of aspirin resistance in patients with AMI would be higher than in patients without AMI. We hypothesized that the prevalence of aspirin resistance in patients with AMI was twice the prevalence in patients without AMI. METHODS: We included 298 consecutive patients with known cardiovascular disease who were admitted to hospital with symptoms suggestive of an AMI. All had been taking aspirin 150 mg/day for at least 7 days prior to hospital admission. Platelet function was measured immediately at admission, and aspirin resistance was defined as a collagen/epinephrine Closure Time (CT(CEPI))<165 s. RESULTS: We found that 70 (23.5%) patients were aspirin resistant, and 70 (23.5%) patients ended up with the diagnosis of an AMI. The prevalence of aspirin resistance was significantly higher in patients with AMI as compared to patients without (36% versus 20%, OR 2.26, CI 95% 1.19-4.22, p=0.0058). The CT(CEPI) measured at admission was an independent factor associated with an AMI. CONCLUSIONS: Aspirin resistance is present in almost one fourth of patients admitted to hospital with symptoms suggestive of an AMI, and aspirin resistance is significantly associated with the diagnosis of a definite AMI.

Using the Platelet Function Analyzer-100 for monitoring aspirin therapy.

INTRODUCTION: The aim of the study was to evaluate the test characteristics of the Platelet Function Analyzer-100 (PFA-100) in patients treated with aspirin. METHODS AND RESULTS: The study consisted of two sub-studies. In study 1, 10 patients with ischemic heart disease (IHD) and 10 controls had platelet function assessed by optical platelet aggregation and the PFA-100 method in two 5-week periods. Patients with IHD were treated with aspirin 150 mg/day (first 5-week period), and 300 mg/day (second 5-week period), whereas the controls only received aspirin (150 mg/day) during the second 5-week period. From the results of study 1, we found that a cut-off value for the PFA-100 collagen/epinephrine cartridge <165 s identified patients not taking aspirin (sensitivity 0.91, specificity 1.00). A good agreement between the PFA-100 method and optical platelet aggregation was found. Within-subject variation for the PFA-100 collagen/epinephrine cartridge was +/-28%, as compared to +/-17% for the optical platelet aggregation. Study 2 included 298 aspirin treated patients who were admitted with symptoms suggestive of an acute myocardial infarction. Platelet function was assessed in duplicate by the PFA-100 collagen/epinephrine cartridge, and a 95% Limit of Agreement interval at [-65%, 65%] indicated a limited precision. CONCLUSION: We defined a cut-off value below which patients not taking aspirin can be identified. However, due to imprecision of the PFA-100 method repeated duplicate assessment of the collagen/epinephrine Closure Time is recommended.