Martijn W. Heymans

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Early prediction of outcome of activities of daily living after stroke: a systematic review

Background and Purpose— Knowledge about robust and unbiased factors that predict outcome of activities of daily living (ADL) is paramount in stroke management. This review investigates the methodological quality of prognostic studies in the early poststroke phase for final ADL to identify variables that are predictive or not predictive for outcome of ADL after stroke. Methods— PubMed, Ebsco/Cinahl and Embase were systematically searched for prognostic studies in which stroke patients were included ⩽2 weeks after onset and final outcome of ADL was determined ≥3 months poststroke. Risk of bias scores were used to distinguish high- and low-quality studies and a qualitative synthesis was performed. Results— Forty-eight of 8425 identified citations were included. The median risk of bias score was 17 out of 27 (range, 6–22) points. Most studies failed to report medical treatment applied, management of missing data, rationale for candidate determinants and outcome cut-offs, results of univariable analysis, and validation and performance of the model, making the predictive value of most determinants indistinct. Six high-quality studies showed strong evidence for baseline neurological status, upper limb paresis, and age as predictors for outcome of ADL. Gender and risk factors such as atrial fibrillation were unrelated to this outcome. Conclusions— Because of insufficient methodological quality of most prognostic studies, the predictive value of many clinical determinants for outcome of ADL remains unclear. Future cohort studies should focus on early prediction using simple models with good clinical performance to enhance application in stroke management and research.

Measurement properties of disease-specific questionnaires in patients with neck pain: a systematic review

PurposeTo critically appraise and compare the measurement properties of the original versions of neck-specific questionnaires.MethodsBibliographic databases were searched for articles concerning the development or evaluation of the measurement properties of an original version of a self-reported questionnaire, evaluating pain and/or disability, which was specifically developed or adapted for patients with neck pain. The methodological quality of the selected studies and the results of the measurement properties were critically appraised and rated using a checklist, specifically designed for evaluating studies on measurement properties.ResultsThe search strategy resulted in a total of 3,641 unique hits, of which 25 articles, evaluating 8 different questionnaires, were included in our study. The Neck Disability Index is the most frequently evaluated questionnaire and shows positive results for internal consistency, content validity, structural validity, hypothesis testing, and responsiveness, but a negative result for reliability. The other questionnaires show positive results, but the evidence for each measurement property is mostly limited, and at least 50% of the information on measurement properties per questionnaire is lacking.ConclusionsOur findings imply that studies of high methodological quality are needed to properly assess the measurement properties of the currently available questionnaires. Until high quality studies are available, we recommend using these questionnaires with caution. There is no need for the development of new neck-specific questionnaires until the current questionnaires have been adequately assessed.

Multiple imputation of missing values was not necessary before performing a longitudinal mixed-model analysis

BACKGROUND AND OBJECTIVES As a result of the development of sophisticated techniques, such as multiple imputation, the interest in handling missing data in longitudinal studies has increased enormously in past years. Within the field of longitudinal data analysis, there is a current debate on whether it is necessary to use multiple imputations before performing a mixed-model analysis to analyze the longitudinal data. In the current study this necessity is evaluated. STUDY DESIGN AND SETTING The results of mixed-model analyses with and without multiple imputation were compared with each other. Four data sets with missing values were created-one data set with missing completely at random, two data sets with missing at random, and one data set with missing not at random). In all data sets, the relationship between a continuous outcome variable and two different covariates were analyzed: a time-independent dichotomous covariate and a time-dependent continuous covariate. RESULTS Although for all types of missing data, the results of the mixed-model analysis with or without multiple imputations were slightly different, they were not in favor of one of the two approaches. In addition, repeating the multiple imputations 100 times showed that the results of the mixed-model analysis with multiple imputation were quite unstable. CONCLUSION It is not necessary to handle missing data using multiple imputations before performing a mixed-model analysis on longitudinal data.

Variable selection under multiple imputation using the bootstrap in a prognostic study

BackgroundMissing data is a challenging problem in many prognostic studies. Multiple imputation (MI) accounts for imputation uncertainty that allows for adequate statistical testing. We developed and tested a methodology combining MI with bootstrapping techniques for studying prognostic variable selection.MethodIn our prospective cohort study we merged data from three different randomized controlled trials (RCTs) to assess prognostic variables for chronicity of low back pain. Among the outcome and prognostic variables data were missing in the range of 0 and 48.1%. We used four methods to investigate the influence of respectively sampling and imputation variation: MI only, bootstrap only, and two methods that combine MI and bootstrapping. Variables were selected based on the inclusion frequency of each prognostic variable, i.e. the proportion of times that the variable appeared in the model. The discriminative and calibrative abilities of prognostic models developed by the four methods were assessed at different inclusion levels.ResultsWe found that the effect of imputation variation on the inclusion frequency was larger than the effect of sampling variation. When MI and bootstrapping were combined at the range of 0% (full model) to 90% of variable selection, bootstrap corrected c-index values of 0.70 to 0.71 and slope values of 0.64 to 0.86 were found.ConclusionWe recommend to account for both imputation and sampling variation in sets of missing data. The new procedure of combining MI with bootstrapping for variable selection, results in multivariable prognostic models with good performance and is therefore attractive to apply on data sets with missing values.

Aetiology and incidence of maxillofacial trauma in Amsterdam: a retrospective analysis of 579 patients

INTRODUCTION The incidence of maxillofacial fractures varies widely between different countries. The large variability in reported incidence and aetiology is due to a variety of contributing factors, including environmental, cultural and socioeconomic factors. This retrospective report presents a study investigating the aetiology and incidence of patients with maxillofacial fractures in Amsterdam over a period of 10 years. RESULTS The study population consisted of 408 males and 171 females with a mean age of 35.9 (SD: ±16.3) years. The age group 20-29 years accounted for the largest subgroup in both sexes. The most common cause of the fractures was traffic related, followed by violence. There were mainly mandibular and zygomatic bone fractures in both males and females, accounting for approximately 80% of all fractures. The main fracture site of the mandible was the combination of mandibular body with mandibular condyle (66 patients; 26.8%), followed by the combination of bilateral condylar fracture and fracture of the symphysis (43 patients; 17.5%). In fractures of the upper 2/3 of the face, zygomatic bone fractures were most common. In patients with alcohol consumption the injury was mostly the result of violence. In conclusion, this report provides important data for the design of plans for injury prevention, as compared with previous studies. Violence related injuries are increasing whereas fractures caused by traffic accidents are decreasing.

Hybrid Imaging Using Quantitative H215O PET and CT-Based Coronary Angiography for the Detection of Coronary Artery Disease

Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H215O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H215O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H215O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H215O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H215O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H215O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H215O PET/CTCA is superior to either H215O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.

Does Growth Hormone Replacement Therapy Reduce Mortality in Adults with Growth Hormone Deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in Adults

CONTEXT Adults with GH deficiency (GHD) have a decreased life expectancy. The effect of GH treatment on mortality remains to be established. OBJECTIVE This nationwide cohort study investigates the effect of GH treatment on all-cause and cause-specific mortality and analyzes patient characteristics influencing mortality in GHD adults. DESIGN, SETTING, AND PATIENTS Patients in the Dutch National Registry of Growth Hormone Treatment in Adults were retrospectively monitored (1985-2009) and subdivided into treatment (n = 2229), primary (untreated, n = 109), and secondary control (partly treated, n = 356) groups. MAIN OUTCOME MEASURES Standardized mortality ratios (SMR) were calculated for all-cause, malignancy, and cardiovascular disease (CVD) mortality. Expected mortality was obtained from cause, sex, calendar year, and age-specific death rates from national death and population counts. RESULTS In the treatment group, 95 patients died compared to 74.6 expected [SMR 1.27 (95% confidence interval, 1.04-1.56)]. Mortality was higher in women than in men. After exclusion of high-risk patients, the SMR for CVD mortality remained increased in women. Mortality due to malignancies was not elevated. In the control groups mortality was not different from the background population. Univariate analyses demonstrated sex, GHD onset, age, and underlying diagnosis as influencing factors. CONCLUSIONS GHD men receiving GH treatment have a mortality rate not different from the background population. In women, after exclusion of high-risk patients, mortality was not different from the background population except for CVD. Mortality due to malignancies was not elevated in adults receiving GH treatment. Next to gender, the heterogeneous etiology is of influence on mortality in GHD adults with GH treatment.

The effectiveness of high-intensity versus low-intensity back schools in an occupational setting: a pragmatic randomized controlled trial.

Study Design. Randomized controlled trial. Objectives. To compare high- and low-intensity back schools with usual care in occupational health care. Summary of Background Data. The content and intensity of back schools vary widely and the methodologic quality of randomized controlled trials is generally weak. Until now, no back school has proven to be superior for workers sick-listed because of subacute nonspecific low back pain. Methods. Workers (n = 299) sick-listed for a period of 3 to 6 weeks because of nonspecific low back pain were recruited by the occupational physician and randomly assigned to a high-intensity back school, a low-intensity back school, or care as usual. Outcome measures were days until return to work, total days of sick-leave, pain, functional status, kinesiophobia, and perceived recovery and were assessed at baseline and at 3 and 6 months of follow-up. Principal analyses were performed according to the intention-to-treat principle. Results. We randomly allocated 299 workers. Workers in the low-intensity back school returned to work faster compared with usual care and the high-intensity back school, with hazard ratios of 1.4 (P = 0.06) and 1.3 (P = 0.09), respectively. The comparison between high-intensity back school and usual care resulted in a hazard ratio of 1.0 (P = 0.83). The median number of sick-leave days was 68, 75, and 85 in the low-intensity back school, usual care, and high-intensity back school, respectively. Beneficial effects on functional status and kinesiophobia were found at 3 months in favor of the low-intensity back school. No substantial differences on pain and perceived recovery were found between groups. Conclusions. The low-intensity back school was most effective in reducing work absence, functional disability, and kinesiophobia, and more workers in this group scored a higher perceived recovery during the 6-month follow-up.

Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome

BACKGROUND Approximately 15-20% of all clinically confirmed pregnancies end in a miscarriage. Intrauterine adhesions (IUAs) are a possible complication after miscarriage, but their prevalence and the contribution of possible risk factors have not been elucidated yet. In addition, the long-term reproductive outcome in relation to IUAs has to be elucidated. METHODS We systematically searched the literature for studies that prospectively assessed the prevalence and extent of IUAs in women who suffered a miscarriage. To be included, women diagnosed with a current miscarriage had to be systematically evaluated within 12 months by hysteroscopy after either spontaneous expulsion or medical or surgical treatment. Studies that included women with a history of recurrent miscarriage only or that evaluated the IUAs after elective abortion or beyond 12 months after the last miscarriage were not included. Subsequently, long-term reproductive outcomes after expectant (conservative), medical or surgical management were assessed in women with and without post-miscarriage IUAs. RESULTS We included 10 prospective studies reporting on 912 women with hysteroscopic evaluation within 12 months of miscarriage and 8 prospective studies, including 1770 women, reporting long-term reproductive outcome. IUAs were detected in 183 women, resulting in a pooled prevalence of 19.1% [95% confidence interval (CI): 12.8-27.5%]. The extent of IUAs was reported in 124 women (67.8%) and was mild, moderate and severe respectively in 58.1, 28.2 and 13.7% of cases. Relative to women with one miscarriage, women with two or three or more miscarriages showed an increased risk of IUAs by a pooled OR of 1.41 and 2.1, respectively. The number of dilatation and curettage (D&C) procedures seemed to be the main driver behind these associations. A total of 150 congenital and acquired intrauterine abnormalities were encountered in 675 women, resulting in a pooled prevalence of 22.4% (95% CI: 16.3-29.9%). Similar reproductive outcomes were reported subsequent to conservative, medical or surgical management for miscarriage, although the numbers of studies and of included women were limited. No studies reported long-term reproductive outcomes following post-miscarriage IUAs. CONCLUSIONS IUAs are frequently encountered, in one in five women after miscarriage. In more than half of these, the severity and extent of the adhesions was mild, with unknown clinical relevance. Recurrent miscarriages and D&C procedures were identified as risk factors for adhesion formation. Congenital and acquired intrauterine abnormalities such as polyps or fibroids were frequently identified. There were no studies reporting on the link between IUAs and long-term reproductive outcome after miscarriage, while similar pregnancy outcomes were reported subsequent to conservative, medical or surgical management. Although this review does not allow strong clinical conclusions on treatment management, it signals an important clinical problem. Treatment strategies are proposed to minimize the number of D&C in an attempt to reduce IUAs.