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.

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.

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.

Physical activity is prospectively associated with spinal pain in children (CHAMPS Study-DK).

ABSTARCT: Spinal pain and physical inactivity are critical public health issues. We investigated the prospective associations of physical activity intensity with spinal pain in children. Physical activity was quantified with accelerometry in a cohort of primary school students. Over 19 months, parents of primary school students reported children's spinal pain status each week via text-messaging (self-reported spinal pain). Spinal pain reports were followed-up by trained clinicians who diagnosed each child's complaint and classified the pain as non-traumatic or traumatic. Associations were examined with logistic regression modeling using robust standard errors and reported with odds ratios (OR). Children (n = 1205, 53.0% female) with mean ± SD age of 9.4 ± 1.4 years, participated in 75,180 weeks of the study. Nearly one-third (31%) of children reported spinal pain, and 14% were diagnosed with a spinal problem. Moderate intensity physical activity was protectively associated with self-reported [OR(95%CI) = 0.84(0.74, 0.95)], diagnosed [OR(95%CI) = 0.79(0.67, 0.94)] and traumatic [OR(95%CI) = 0.77(0.61, 0.96)] spinal pain. Vigorous intensity physical activity was associated with increased self-reported [OR(95%CI) = 1.13(1.00, 1.27)], diagnosed [OR(95%CI) = 1.25(1.07, 1.45)] and traumatic [OR(95%CI) = 1.28(1.05, 1.57)] spinal pain. The inclusion of age and sex covariates weakened these associations. Physical activity intensity may be a key consideration in the relationship between physical activity behavior and spinal pain in children.

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.

Physical activity in children attending preschools.

OBJECTIVE: To identify correlates of objectively measured moderate and vigorous physical activity (MVPA) in children during preschool attendance. METHODS: This cross-sectional study included data from 426 apparently healthy Danish children (49.5% boys), 5 to 6 years of age enrolled in 42 randomly selected preschools. The percentage of time spent in MVPA (≥ 574 counts/15 second) during preschool attendance was measured using ActiGraph accelerometers over 4.3 preschool days in May and June in 2009. Thirty-seven potential correlates across the child, preschool staff, and preschool environment domains were tested for associations with MVPA. RESULTS: The final multivariate model identified 9 significant correlates of MVPA. Preterm birth, vegetation on the playground, and rainy days were negatively associated with MVPA, whereas child motor coordination, location of preschool building on the playground, gender (boys), percentage afternoon hours, and size of indoor area per child were positively associated with MVPA. The direction of the significant association with the parental mean education level was unclear. CONCLUSIONS: We identified a number of new modifiable correlates of MVPA during preschool attendance. The positive association with size of indoor area per child and location of the preschool building on the playground seem important correlates to be targeted in future studies.

Interpretation of subgroup effects in published trials.

With the rapidly expanding number of studies reporting on treatment subgroups come new challenges in analyzing and interpreting this sometimes complex area of the literature. This article discusses 3 important issues regarding the analysis and interpretation of existing trials or systematic reviews that report on treatment effect modifiers (subgroups) for specific physical therapy interventions. The key messages are: (1) point estimates of treatment modifier effect size (interaction effect) and their confidence intervals can be calculated using group-level data when individual patient-level data are not available; (2) interaction effects do not define the total effect size of the intervention in the subgroup but rather how much more effective it is in the subgroup than in those not in the subgroup; (3) recommendations regarding the use of an intervention in a subgroup need to consider the size and direction of the main effect and the interaction effect; and (4) rather than simply judging whether a treatment modifier effect is clinically important based only on the interaction effect size, a better criterion is to determine whether the combined effect of the interaction effect and main effect makes the difference between an overall effect that is clinically important and one that is not clinically important.

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.

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.

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.

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.

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.

Generalizability of a composite student selection procedure at a university-based chiropractic program.

PURPOSE: Non-cognitive admission criteria are typically used in chiropractic student selection to supplement grades. The reliability of non-cognitive student admission criteria in chiropractic education has not previously been examined. In addition, very few studies have examined the overall test generalizability of composites of non-cognitive admission variables in admission to health science programs. The aim of this study was to estimate the generalizability of a composite selection to a chiropractic program, consisting of: application form information, a written motivational essay, a common knowledge test, and an admission interview. METHODS: Data from 105 Chiropractic applicants from the 2007 admission at the University of Southern Denmark 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 method. The reliability of obtained applicant ranks (generalizability coefficients) was calculated for the individual admission criteria and for the composite admission procedure. RESULTS: Very good generalizability was found for the common knowledge test (G=1.00) and the admission interview (G=0.88). Good generalizability was found for application form information (G=0.75) and moderate generalizability (G=0.50) for the written motivation essay. The generalizability of the final composite admission procedure, which was a weighted composite of all 4 admission variables was good (G(c) = 0.80). CONCLUSION: Good generalizability for a composite admission to a chiropractic program was found. Optimal weighting and adequate sampling are important for obtaining optimal generalizability. Limitations and suggestions for future research are discussed.

Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes.

OBJECTIVE: To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality). RESEARCH DESIGN AND METHODS: Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes. RESULTS: The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%. CONCLUSIONS: These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.

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.

Burned-out discs stop hurting: fact or fiction?

STUDY DESIGN: Cross-sectional study of a general-population sample. OBJECTIVE: The aim was to test the hypothesis that moderate disc degeneration (DD) is stronger associated with low back pain (LBP) than severe degeneration, and also to identify a possible dose-response relationship between numbers of degenerated discs and LBP. SUMMARY OF BACKGROUND DATA: Among many clinicians there has been a belief that DD initially causes pain because of the penetration of fluid nuclear material through annular fissures, and that pain eventually resolves as the nucleus becomes fibrotic and can no longer penetrate the fissures. METHODS: From a population-based cohort of 412 individuals, all aged 40, three groups were created for a primary analysis: those with exclusively normal discs (white nuclei on a T2-weighted MRI), those with moderate DD (grey) + normal, and those with severely degenerated (black) + normal discs. The number of individuals reporting LBP during the past year (the most relevant for chronic/intermittent pain) and the past month were separately related to DD. Second, a possible dose-response in terms of numbers of abnormal discs was analyzed. RESULTS: The percentage of people with LBP was virtually not influenced by grey discs, where the fraction with pain during the past year was close to 69% irrespective of the presence or number of grey discs. Black discs, however, increased the corresponding fraction from 60%, if no black discs, to 86% for those with 2 (odds ratio of 2 per number of black disc). The risk for LBP during the past year attributed to black discs was 11%. CONCLUSION: The data could not support the hypothesis that severely degenerated discs are "burned out" and become less painful. People with black discs had a higher prevalence of LBP compared to those with grey or normal discs, the latter 2 being equally often painful.