Optimizing fracture prevention: the fracture liaison service, an observational study.

UNLABELLED: The response rate to the invitation to the fracture liaison service and reasons for non-response were evaluated in 2,207 fragility fracture patients. Fifty-one percent responded; non-responders were most often not interested (38 %) or were hip fracture patients. After 1 year of treatment, 88 % was still persistent and 2 % had a new fracture. INTRODUCTION: To increase the percentage of elderly fracture patients undergoing a dual energy x-ray absorptiometry (DXA) measurement, and to investigate why some patients did not respond to invitation to our fracture liaison service (FLS). METHODS: In four Dutch hospitals, fracture patients ≥ 50 years were invited through a written or personal invitation at the surgical outpatient department, for a DXA measurement and visit to our FLS. Patients who did not respond were contacted by telephone. In patients diagnosed with osteoporosis, treatment was started. Patients were contacted every 3 months during 1 year to assess drug persistence and the occurrence of subsequent fractures. RESULTS: Of the 2,207 patients who were invited, 50.6 % responded. Most frequent reasons for not responding included: not interested (38 %), already screened/under treatment for osteoporosis (15.7 %), physically unable to attend the clinic (11.5 %), and death (5.2 %). Hip fracture patients responded less frequently (29 %) while patients with a wrist (60 %) or ankle fracture (65.2 %) were more likely to visit the clinic. In 337 responding patients, osteoporosis was diagnosed and treatment was initiated. After 12 months of follow-up, 88 % of the patients were still persistent with anti-osteoporosis therapy and only 2 % suffered a subsequent clinical fracture. CONCLUSION: In elderly fracture patients, the use of a FLS leads to an increased response rate, a high persistence to drug treatment, and a low rate of subsequent clinical fractures. Additional programs for hip fracture patients are required, as these patients have a low response rate.

Association of P2X7 receptor polymorphisms with bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients.

UNLABELLED: The P2X7 receptor is thought to be involved in bone physiology in a pro-osteogenic manner. Therefore, we examined associations between genetic variations in the P2X7 receptor gene and bone mineral density (BMD). We found an association between four non-synonymous polymorphism of the human P2X7 receptor and the risk of osteoporosis. INTRODUCTION: The purpose of this study was to determine whether genetic variation in the P2X7 receptor gene (P2RX7) is associated with decreased BMD and risk of osteoporosis in fracture patients. METHODS: Six hundred ninety women and 231 men aged≥50 years were genotyped for 15 non-synonymous P2RX7 SNPs. BMD was measured at the total hip, lumbar spine and femoral neck. RESULTS: Four non-synonymous SNPs were associated with BMD. The Ala348Thr gain-of-function polymorphism was associated with increased BMD values at the lumbar spine (p=0.012). Decreased hip BMD values were associated with two loss-of-function SNPs in the P2RX7, i.e., in subjects homozygous for the Glu496Ala polymorphism as well as in subjects carrying at least one variant allele of the Gly150Arg polymorphism (p=0.018 and p=0.011; respectively). In men, we showed that subjects either heterozygous or homozygous for the Gln460Arg gain-of-function polymorphism in the P2RX7 had a significantly 40% decrease in risk of a lower T-score value (OR=0.58 [95%CI, 0.33-1.00]). CONCLUSION: Thus, genetic aberrations of P2X7R function are associated with lower BMD and increased osteoporosis risk. Therefore, detection of non-synonymous SNPs within the P2RX7 might be useful for osteoporosis risk estimation at an early stage, potentially enabling better osteoporosis prevention and treatment.

Cost-effectiveness of nutritional intervention in elderly subjects after hip fracture. A randomized controlled trial.

UNLABELLED: Hip fracture patients can benefit from nutritional supplementation during their recovery. Up to now, cost-effectiveness evaluation of nutritional intervention in these patients has not been performed. Costs of nutritional intervention are relatively low as compared with medical costs. Cost-effectiveness evaluation shows that nutritional intervention is likely to be cost-effective. INTRODUCTION: Previous research on the effect of nutritional intervention on clinical outcome in hip fracture patients yielded contradictory results. Cost-effectiveness of nutritional intervention in these patients remains unknown. The aim of this study was to evaluate cost-effectiveness of nutritional intervention in elderly subjects after hip fracture from a societal perspective. METHODS: Open-label, multi-centre randomized controlled trial investigating cost-effectiveness of intensive nutritional intervention comprising regular dietetic counseling and oral nutritional supplementation for 3 months postoperatively. Patients allocated to the control group received care as usual. Costs, weight and quality of life were measured at baseline and at 3 and 6 months postoperatively. Incremental cost-effectiveness ratios (ICERs) were calculated for weight at 3 months and quality adjusted life years (QALYs) at 6 months postoperatively. RESULTS: Of 152 patients enrolled, 73 were randomized to the intervention group and 79 to the control group. Mean costs of the nutritional intervention was 613 Euro. Total costs and subcategories of costs were not significantly different between both groups. Based on bootstrapping of ICERs, the nutritional intervention was likely to be cost-effective for weight as outcome over the 3-month intervention period, regardless of nutritional status at baseline. With QALYs as outcome, the probability for the nutritional intervention being cost-effective was relatively low, except in subjects aged below 75 years. CONCLUSION: Intensive nutritional intervention in elderly hip fracture patients is likely to be cost-effective for weight but not for QALYs. Future cost-effectiveness studies should incorporate outcome measures appropriate for elderly patients, such as functional limitations and other relevant outcome parameters for elderly.

What is the long-term clinical outcome after fragility fractures of the pelvis? - A CT-based cross-sectional study.

BACKGROUND: Recently, Rommens and Hoffman introduced a CT-based classification system for fragility fractures of the pelvis (FFP). Although fracture characteristics have been described, the relationship with clinical outcome is lacking. The purpose of this study was to get insight into the type of treatment and subsequent clinical outcome after all types of FFP. METHODS: A cross-sectional cohort study was performed including all elderly patients (≥ 65 years) with a CT-diagnosed FFP, between 2007-2019 in two level 1 trauma centers. Data regarding treatment, mortality and clinical outcome was gathered from the electronic patient files. Patients were asked to complete patient-reported outcome measures (PROMs) regarding physical functioning (SMFA) and quality of life (EQ-5D). Additionally, a standardized multidisciplinary treatment algorithm was constructed. RESULTS: A total of 187 patients were diagnosed with an FFP of whom 117 patients were available for follow-up analysis and 58 patients responded. FFP type I was most common (60%), followed by type II (27%), type III (8%) and type IV (5%). Almost all injuries were treated non-operatively (98%). Mobility at six weeks ranged from 50% (type III) to 80% type II). Mortality at 1 year was respectively 16% (type I and II), 47% (type III) and 13% (type IV). Physical functioning (SMFA function index) ranged from 62 (type III and IV) to 69 (type II) and was significantly decreased (P=<0.001) compared to the age-matched general population. Quality of life was also significantly decreased, ranging from 0.26 (type III) to 0.69 (type IV). CONCLUSIONS: FFP type I and II are most common. Treatment is mainly non-operative, resulting in good mobility after six weeks, especially for patients with FFP type I and II. Mortality rates at one year were substantial in all patients. Physical functioning and quality of life was about 20-30% decreased compared to the general population.

Implementation of osteoporosis guidelines: a survey of five large fracture liaison services in the Netherlands.

SUMMARY: Implementation of case findings according to guidelines for osteoporosis in fracture patients presenting at a Fracture Liaison Service (FLS) was evaluated. Despite one guideline, all FLSs differed in the performance of patient selection and prevalence of clinical risk factors (CRFs) indicating the need for more concrete and standardised guidelines. INTRODUCTION: The aim of the study was to evaluate the implementation of case findings according to guidelines for osteoporosis in fracture patients presenting at FLSs in the Netherlands. METHODS: Five FLSs were contacted to participate in this prospective study. Patients older than 50 years with a recent clinical fracture who were able and were willing to participate in fracture risk evaluation were included. Performance was evaluated by criteria for patient recruitment, patient characteristics, nurse time, evaluated clinical risk factors (CRFs), bone mineral density (BMD) and laboratory testing and results of CRFs and BMD are presented. Differences between FLSs were analysed for performance (by chi-square and Student's t test) and for prevalence of CRFs (by relative risks (RR)). RESULTS: All FLSs had a dedicated nurse spending 0.9 to 1.7 h per patient. During 39 to 58 months follow-up, 7,199 patients were evaluated (15 to 47 patients/centre/month; mean age, 67 years; 77% women). Major differences were found between FLSs in the performance of patient recruitment, evaluation of CRFs, BMD and laboratory testing, varying between 0% and 100%. The prevalence of CRFs and osteoporosis varied significantly between FLSs (RR between 1.7 and 37.0, depending on the risk factor). CONCLUSION: All five participating FLSs with a dedicated fracture nurse differed in the performance of patient selection, CRFs and in the prevalence of CRFs, indicating the need for more concrete and standardised guidelines to organise evaluation of patients at the time of fracture in daily practice.

Risk of subsequent fracture and mortality within 5 years after a non-vertebral fracture.

SUMMARY: The absolute 5-year risk of subsequent non-vertebral fractures (NVFs) in 1,921 patients presenting with a NVF was 17.6% and of mortality was 32.3%. These risks were highest within the first year, indicating the need to study which reversible factors can be targeted to immediately minimise subsequent fracture risk and mortality. INTRODUCTION: NVFs are the most frequent clinical fractures in patients presenting at the emergency unit because of a clinical fracture. The aim of the study was to determine the 5-year absolute risk (AR) of subsequent NVF and mortality in patients at the time they present with a NVF. METHODS: Between 1999 and 2001, 1,921 consecutive patients 50+ years from a level 1 trauma centre were included. All NVFs were confirmed on radiograph reports, and mortality was checked in the national obituary database. Available potential risk factors for a subsequent NVF and mortality (age, sex and baseline fracture location: major-hip, pelvis, multiple ribs, proximal tibia/humerus and distal femur; minor-all others) were expressed as hazard ratios (HR) with 95% confidence intervals (CI) using multivariable Cox regression analysis. RESULTS: The AR for a subsequent NVF was 17.6% and was related to age (HR per decade, 1.44; 95%CI, 1.29-1.60). The AR for mortality was 32.3% and was related to age (HR per decade, 2.59; 95%CI, 2.37-2.84), male sex (HR, 1.74; 95%CI, 1.44-2.10), major fracture at baseline (HR, 5.56; 95%CI, 3.48-8.88; not constant over time) and subsequent fracture (HR, 1.65; 95%CI, 1.33-2.05). The highest risks were found within the first year (NVFs, 6.4%; mortality, 12.2%) and were related to age and, in addition, to baseline fracture location for mortality. CONCLUSIONS: Within 5 years after an initial NVF, nearly one in five patients sustained a subsequent NVF and one in three died. One third of subsequent NVFs and mortality occurred within 1 year, indicating the need to study which reversible factors can be targeted to immediately prevent subsequent fractures and mortality.

Clinical subsequent fractures cluster in time after first fractures.

OBJECTIVES: The risk of subsequent fractures is double the risk of having a first fracture. We analysed whether this risk is constant or not over time. METHODS: A population-based study in 4140 postmenopausal women, aged between 50 and 90 years, on radiographic confirmed clinical fractures from menopause onwards analysed by Cox regression. RESULTS: A total of 924 (22%) women had a first fracture and 243 (26% of 924) a subsequent fracture. Of all first fractures, 4% occurred in each year from menopause onwards, while after a first fracture 23% of all subsequent fractures occurred within 1 year and 54% within 5 years. When calculated from time of first fracture, the relative risk (RR) of subsequent fracture was 2.1 (95% CI 1.7 to 2.6) and remained increased over 15 years. When calculated for specific time intervals after a first fracture, the RR was 5.3 (95% CI 4.0 to 6.6) within 1 year, 2.8 (95% CI 2.0 to 3.6) within 2-5 years, 1.4 (95% CI 1.0 to 1.8) within 6-10 years and 0.41 (95% CI 0.29 to 0.53) after >10 years. CONCLUSIONS: From menopause onwards, clinical fractures cluster in time, indicating the need for early action to prevent subsequent fractures.

Regulation of CXCL16 expression and secretion by myeloid cells is not altered in rheumatoid arthritis.

OBJECTIVE: Chemokine (C-X-C motif) ligand 16 (CXCL16) is secreted by macrophages and dendritic cells (DCs) to attract memory type T cells. CXCL16 expression is increased in arthritic joints of patients with rheumatoid arthritis (RA) and a role for CXCL16 has been suggested in the pathogenesis of RA. To date, little is known about the regulation of CXCL16 on monocytes/macrophages and DCs. The aim of this study was to elucidate how CXCL16 expression is regulated in healthy donors and patients with RA. METHODS: CD14+cells were isolated from the peripheral blood or synovial fluid of patients with RA and healthy controls, differentiated into different types of dendritic cells or macrophages and stimulated with various cytokines or lipopolysaccharide (LPS). Cell surface proteins, including surface CXCL16, were measured by flow cytometry and soluble CXCL16 was measured by ELISA. RESULTS: Distinct types of dendritic cells constitutively express and secrete CXCL16, which is not affected by maturation. Monocytes rapidly upregulate membrane-bound CXCL16 expression and release soluble CXCL16 upon culture. CXCL16 expression by monocytes is transiently inhibited by the Toll-like receptor (TLR)4 ligand LPS. Th2 type cytokines inhibit soluble CXCL16, whereas T helper (Th)1 cell stimulus enhances its release. In RA monocytes/macrophages, neither CXCL16 expression, nor CXCL16 regulation is different from healthy controls. CONCLUSIONS: Culture of monocytes is the main trigger for CXCL16 surface expression in vitro, which is not altered in RA. Together our data suggest that the increased CXCL16 expression in patients with RA is likely to be caused by increased influx of monocytes rather than intrinsic differences in CXCL16 regulation.

Is function of the Drosophila homeotic gene Ultrabithorax canalized?

Genetic variation affecting the expressivity of an amorphic allele of the homeotic gene Ultrabithorax, (Ubx1) was characterized after 11 generations of introgression into 29 different isofemale lines. Heterozygotes display a range of haploinsufficient phenotypes, from overlap with wild-type halteres to dramatic transformations such as a 50% increase in area and the presence of over 20 bristles on the anterior margin of each haltere. In both the wild-type and mutant genetic backgrounds, there is moderate genetic variance and low environmental variance/developmental asymmetry, as expected of a trait under stabilizing selection pressure. Surprisingly, there is little evidence that mutant halteres are more variable than wild-type ones, so it is unclear that haltere development is also canalized. The correlation between wild-type and Ubx haltere size is very low, indicating that interactions among modifiers of Ubx are complex, and in some cases sex-specific. The potential quantitative genetic contributions of homeotic genes to appendage morphology are discussed, noting that population-level effects of variation in key regulatory genes may be prevalent and complex but cannot be readily extrapolated to macroevolutionary diversification.

Potential variance affecting homeotic Ultrabithorax and Antennapedia phenotypes in Drosophila melanogaster.

Introgression of homeotic mutations into wild-type genetic backgrounds results in a wide variety of phenotypes and implies that major effect modifiers of extreme phenotypes are not uncommon in natural populations of Drosophila. A composite interval mapping procedure was used to demonstrate that one major effect locus accounts for three-quarters of the variance for haltere to wing margin transformation in Ultrabithorax flies, yet has no obvious effect on wild-type development. Several other genetic backgrounds result in enlargement of the haltere significantly beyond the normal range of haploinsufficient phenotypes, suggesting genetic variation in cofactors that mediate homeotic protein function. Introgression of Antennapedia produces lines with heritable phenotypes ranging from almost complete suppression to perfect antennal leg formation, as well as transformations that are restricted to either the distal or proximal portion of the appendage. It is argued that the existence of "potential" variance, which is genetic variation whose effects are not observable in wild-type individuals, is a prerequisite for the uncoupling of genetic from phenotypic divergence.

The conformational behaviour of complexes of alpha-cyclodextrin with p-chlorophenol and p-hydroxybenzoic acid in water as studied by molecular dynamics simulations.

Molecular dynamics simulations were performed to obtain information about the conformational behaviour and stabilization of alpha-cyclodextrin (alpha CD) complexes in water. Simulations of p-chlorophenol and p-hydroxybenzoic acid in alpha CD showed that the complex is a very flexible system. The guest compound rotates inside the cavity and partly moves in and out. alpha CD continuously adapts its conformation to the orientation of the guest compound (or vice versa): the hexagon of the glycosidic oxygen atoms is stretched parallel to the plane of the aromatic ring of the guest compound during 80% of the simulation. This suggests that Van der Waals interactions play an important role in the stabilization of the complex. Each intramolecular hydrogen bond between neighbouring glucose units is formed during 30-80% of the simulation. Hydrogen bonds between alpha CD and the guest compound, on the other hand, are rarely formed. Thus, intermolecular hydrogen bonding seems to play a minor role in the stabilization of alpha CD complexes.

Revision of laparoscopic adjustable gastric banding: success or failure?

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a safe and frequently performed bariatric procedure. Unfortunately, re-operations are often necessary. Reports on the success of revisional procedures are scarce and show variable results, either supporting or declining the idea of revising LAGB. This study describes a large cohort of re-operations after failed LAGB to determine the success of revision. METHODS: By use of a prospective cohort, all LAGB revisions performed between 1996 and 2008 were identified. From 301 primary LAGB procedures in our centre, 43 patients (14.3%) required a band revision. In addition, 51 patients were referred from other centres. Our analysis included in total 94 patients with a mean follow-up period of 38 months after revision. RESULTS: Revision was mainly necessary due to anterior slippage (46%) and symmetrical pouch dilatation (36%), which could be resolved by replacing (70%) or refixating the band (27%). Weight loss significantly increased after revision (excess BMI loss (EBMIL), 37.2 ± 36.3% versus 47.5 ± 30.4%, P < 0.05). After revision, 23 patients (24%) needed a second re-operation. Patients converted to other procedures (16%) during the second re-operation showed larger weight loss than the revised group (EBMIL, 64.3 ± 28.1% versus 44.3 ± 28.7%, P < 0.05). CONCLUSIONS: We report on a large cohort of LAGB revisions with 38 months of follow-up. Revision of failed LAGB by either refixation or replacement of the band is successful and further increases weight loss.

Osteoporosis is not a risk factor for the development of nonunion: A cohort nested case-control study.

INTRODUCTION: Osteoporosis (OP) is one of the most prevalent metabolic bone disorders worldwide and it is associated with a higher incidence of fractures. The aim of this study was to identify OP as a risk factor for the development of nonunion. METHODS: In a prospective database all patients aged >50 years with an acute fracture were screened for osteoporosis from September 13, 2004 till February 9, 2009. Bone mineral density measurements (T-scores, Z-scores and absolute values in g/cm(2)) were performed. The selected patients were matched (1:2 ratio) to control patients based on gender, age (±5 years) and type of fracture according to the AO-criteria. Other parameters including diabetes mellitus, corticosteroid use, rheumatoid arthritis, smoking, alcohol use, and body mass index were recorded. Follow-up for the patients in the matched group was at least one year. RESULTS: This study included a total of 1498 patients who were screened for the presence of osteoporosis. In total 40 patients were treated for nonunion. After 1:2 matching this resulted in a total number of 120 patients for analysis. Logistic regression analysis including all covariates in the model demonstrated no correlation between the standardised regression coefficients and the development of nonunion (r(2)=0.10, p=0.6). The patients that developed an atrophic nonunion, according to radiographic results, were analysed separately and compared to matched patients. The presence of osteoporosis, osteopenia and normal bone density and the related independent BMD measurements did not differ significantly between the atrophic nonunion group and the matched controls. CONCLUSION: We conclude that although bone quality may be diminished in the elderly this does not influence the occurrence of nonunion. These results indicate that the use of BMD measurements preoperatively to identify osteoporosis as a possible risk factor of nonunion has no clinical value.

Ten-year mortality among hospitalised patients with fractures of the pubic rami.

In a case-control study, 99 patients aged over 60 years and admitted to hospital with an isolated single fracture of the pubic ramus were compared with age- and gender-matched patients without fractures, in terms of morbidity and mortality. Ten years of follow-up showed that the survival of patients with an isolated pubic ramus fracture was significantly lower than that of controls. The mortality rates of patients with isolated pubic ramus fractures at 1, 5 and 10 years were 24.7%, 64.4% and 93.8%, respectively. One-third of the mortality was due to cardiovascular events. A 20.2% complication rate was found during hospital admission, mainly caused by infectious diseases, including urinary tract infection and pneumonia. Thirty-three percent of the patients were temporarily or permanently admitted to a nursing home, because they were unable to mobilise independently. In conclusion, our study found significant morbidity and mortality among patients admitted to hospital for an isolated pubic ramus fracture, both during hospital admission and during 10 years of follow-up.

Microsurgical vasoepididymostomy in the treatment of occlusive azoospermia.

OBJECTIVE: To evaluate the practice and outcome of the end-to-end and end-to-side techniques of vasoepididymostomy for the treatment of occlusive azoospermia. PATIENTS AND METHODS: This retrospective study comprised 31 unselected patients (mean age 32 years, range 22-59) operated on with one of two techniques, more usually a modified end-to-side technique. Sperm quality and paternity were assessed in 24 patients during a 2-year follow-up. RESULTS: Of the 15 patients in whom sperm were found at anastomosis, sperm were retrieved from 11. Of 24 patients, 11 had patent anastomoses and paternity was achieved in three cases. CONCLUSION: Although performed by a proficient microsurgeon the operative success rate was low, partly because the operation was technically demanding but largely because of the difficulty in assessing intraoperatively the level of occlusion and the quality of the sperm. Better techniques for the evaluation of sperm during the operation should be developed.

Factors influencing peak expiratory flow in teenage boys.

BACKGROUND: Peak expiratory flow (PEF) is a useful measure of pulmonary health status and is frequently utilised in asthma management. Reduction in PEF is usually indicative of onset of asthma symptoms. However, use can be made of PEF values only if normal values are known. The definition of normal range is always difficult and may vary between regions and be affected by a variety of factors. OBJECTIVE: To establish PEF values for teenage boys in a Cape Town suburb and examine factors that possibly influence this measurement. SETTING: A high school for boys in the southern suburbs of Cape Town. METHODS: Measurements of PEF were taken for 124 boys. Subjects were approximately 16 years old and apparently healthy at the time of survey. Further details were provided by means of a questionnaire. RESULTS: PEF ranged from 350 to 760 l/min, with a mean (+/- standard deviation (SD)) of 539 +/- 68 l/min. Factors expected to influence PEF included height and mass, whereas unexpected factors included sport intensity and academic grade. A trend to reduced peak flow was already evident in boys who smoked and boys from homes where a parent smoked. Regression analysis suggested peak flow differences in our population compared with the standard reference. CONCLUSION: Interpretation of results obtained from peak-flow instruments should take into account additional knowledge concerning the individual. Further surveys of the South African population and of different groups should be done to establish local standards and factors influencing PEF.

Modeling and conformation analysis of beta-cyclodextrin complexes.

A series of beta-cyclodextrin complexes containing various guest molecules was studied using computer-aided molecular modeling and conformation analysis techniques. The geometry of each complex was studied using crystallographic data. The positions of the glycosidic O4 atoms indicate that the beta-cyclodextrin molecules are elliptically distorted. This distortion can be related to the van der Waals volume of the guest molecules. This correlation is different for aromatic and non-aromatic guest compounds. Rigid body docking experiments demonstrated that in crystal structures the guest molecule occupies a position in the cavity of nearly minimum interaction energy when there are no other molecules having interactions with the guest molecule. From the crystallographic data several rules could be deduced which seem to determine the conformation of beta-cyclodextrin molecules in complexes. A procedure was developed to construct beta-cyclodextrin molecules that are able to encompass guest molecules having a given van der Waals volume.

Quantitative structure-activity relationship studies of progesterone receptor binding steroids.

The selection of appropriate descriptors is an important step in the successful formulation of quantitative structure-activity relationships (QSARs). This paper compares a number of feature selection routines and mapping methods that are in current use. They include forward stepping regression (FSR), genetic function approximation (GFA), generalized simulated annealing (GSA), and genetic neural network (GNN). On the basis of a data set of steroids of known in vitro binding affinity to the progsterone receptor, a number of QSAR models are constructed. A comparison of the predictive qualities for both training and test compounds demonstrates that the GNN protocol achieves the best results among the 2D QSAR that are considered. Analysis of the choice of descriptors by the GNN method shows that the results are consistent with established SARs on this series of compounds.