Prediction of Osteoporotic Hip Fracture Outcome: Comparative Accuracy of 27 Immune-Inflammatory-Metabolic Markers and Related Conceptual Issues.

Objectives: This study, based on the concept of immuno-inflammatory-metabolic (IIM) dysregulation, investigated and compared the prognostic impact of 27 indices at admission for prediction of postoperative myocardial injury (PMI) and/or hospital death in hip fracture (HF) patients. Methods: In consecutive HF patient (n = 1273, mean age 82.9 ± 8.7 years, 73.5% females) demographics, medical history, laboratory parameters, and outcomes were recorded prospectively. Multiple logistic regression and receiver-operating characteristic analyses (the area under the curve, AUC) were used to establish the predictive role for each biomarker. Results: Among 27 IIM biomarkers, 10 indices were significantly associated with development of PMI and 16 were indicative of a fatal outcome; in the subset of patients aged >80 years with ischaemic heart disease (IHD, the highest risk group: 90.2% of all deaths), the corresponding figures were 26 and 20. In the latter group, the five strongest preoperative predictors for PMI were anaemia (AUC 0.7879), monocyte/eosinophil ratio > 13.0 (AUC 0.7814), neutrophil/lymphocyte ratio > 7.5 (AUC 0.7784), eosinophil count < 1.1 × 109/L (AUC 0.7780), and neutrophil/albumin × 10 > 2.4 (AUC 0.7732); additionally, sensitivity was 83.1-75.4% and specificity was 82.1-75.0%. The highest predictors of in-hospital death were platelet/lymphocyte ratio > 280.0 (AUC 0.8390), lymphocyte/monocyte ratio < 1.1 (AUC 0.8375), albumin < 33 g/L (AUC 0.7889), red cell distribution width > 14.5% (AUC 0.7739), and anaemia (AUC 0.7604), sensitivity 88.2% and above, and specificity 85.1-79.3%. Internal validation confirmed the predictive value of the models. Conclusions: Comparison of 27 IIM indices in HF patients identified several simple, widely available, and inexpensive parameters highly predictive for PMI and/or in-hospital death. The applicability of IIM biomarkers to diagnose and predict risks for chronic diseases, including OP/OF, in the preclinical stages is discussed.

Persistence of Detectable Anti-Pneumococcal Antibodies 4 Years After Pneumococcal Polysaccharide Vaccination in a Randomised Controlled Trial: The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE).

AIM: Mouse models have indicated that the pneumococcal polysaccharide vaccine (PPV) can reduce atherosclerosis. This is probably through a process of molecular mimicry, where phosphorylcholine in the capsular polysaccharide of the vaccine elicits antibodies that cross-react with oxidised low-density lipoprotein and reduce plaque. We investigated whether a similar mechanism occurs in humans. METHODS: A large national blinded, randomised, placebo-controlled trial of the PPV (Australian Study for the Prevention through Immunisation of Cardiovascular Events [AUSPICE]) is underway with fatal and nonfatal cardiovascular disease (CVD) events as the primary outcome. Participants at one centre agreed to a substudy measuring a number of biomarkers and surrogates of CVD over 4 years, including anti-pneumococcal antibodies (immunoglobulin G and immunoglobulin M), C-reactive protein, carotid intima-media thickness, pulse wave velocity, insulin, fasting blood glucose, glycated haemoglobin, and hepatorenal index. RESULTS: Antipneumococcal immunoglobulin G and immunoglobulin M were both present and statistically significantly increased in the treated group compared to control at 4 years. However, there were no differences in any of the surrogate measures of CVD or metabolic markers at 4 years. CONCLUSIONS: While there were prolonged differences in anti-pneumococcal antibody titres following PPV vaccination, these did not appear to provide any cardioprotective effect, as measured by a range of markers. Final results using the fatal and nonfatal CVD events await the completion of national health record linkage next year. TRIAL REGISTRATION: ACTRN12615000536561.

Comparison of Prognostic Value of 10 Biochemical Indices at Admission for Prediction Postoperative Myocardial Injury and Hospital Mortality in Patients with Osteoporotic Hip Fracture.

Aim: To evaluate the prognostic impact at admission of 10 biochemical indices for prediction postoperative myocardial injury (PMI) and/or hospital death in hip fracture (HF) patients. Methods: In 1273 consecutive patients with HF (mean age 82.9 ± 8.7 years, 73.5% women), clinical and laboratory parameters were collected prospectively, and outcomes were recorded. Multiple logistic regression and receiver-operating characteristic analyses (the area under the curve, AUC) were preformed, the number needed to predict (NNP) outcome was calculated. Results: Age ≥ 80 years and IHD were the most prominent clinical factors associated with both PMI (with cardiac troponin I rise) and in-hospital death. PMI occurred in 555 (43.6%) patients and contributed to 80.3% (49/61) of all deaths (mortality rate 8.8% vs. 1.9% in non-PMI patients). The most accurate biochemical predictive markers were parathyroid hormone > 6.8 pmol/L, urea > 7.5 mmol/L, 25(OH)vitamin D < 25 nmol/L, albumin < 33 g/L, and ratios gamma-glutamyl transferase (GGT) to alanine aminotransferase > 2.5, urea/albumin ≥ 2.0 and GGT/albumin ≥ 7.0; the AUC for developing PMI ranged between 0.782 and 0.742 (NNP: 1.84−2.13), the AUC for fatal outcome ranged from 0.803 to 0.722, (NNP: 3.77−9.52). Conclusions: In HF patients, easily accessible biochemical indices at admission substantially improve prediction of hospital outcomes, especially in the aged >80 years with IHD.

Generation of cardio-protective antibodies after pneumococcal polysaccharide vaccine: Early results from a randomised controlled trial.

BACKGROUND AND AIMS: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. METHODS: A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). RESULTS: Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. CONCLUSIONS: PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.

Usefulness of simple biomarkers at admission as independent indicators and predictors of in-hospital mortality in older hip fracture patients.

INTRODUCTION: The data on predictive value of the routinely obtained preoperative biochemical parameters in hip fracture (HF) patients are limited. The aims of this study were to examine in older HF patients (1) the relationships between a broad set of routine laboratory parameters at admission and in-hospital mortality, and (2) evaluate the prognostic value the biomarkers and clinical characteristics (alone or in combination) provide to predict a fatal outcome. PATIENTS AND METHODS: In 1820 consecutive patients with low-trauma osteoporotic HF aged >60 years (mean age 82.8 ±â€¯8.1 years; 76.4% women; 65% community-dwelling) 35 laboratory variables along with 20 clinical and socio-demographic characteristics at admission were analysed. The validation cohort included data on 455 older (≥60 years of age) HF patients (mean age 82.1 ±â€¯8.0 years, 72.1% women). RESULTS: The mortality rate was 6% (n = 109). On univariate analysis 14 laboratory and 8 clinical parameters have been associated with in-hospital mortality. Multiple regression analyses determined 7 variables at admission as independent indicators of a fatal outcome: 4 biomarkers (albumin <33 g/L; alanine aminotransferase/gamma-glutamyl transferase ratio [GGT/ALT] >2.5; parathyroid hormone [PTH] >6.8 pmol/L; 25(OH)vitamin D < 25 nmol/L) and 3 pre-fracture clinical conditions (history of myocardial infarction, chronic kidney disease [GFR <60 ml/min/1.73 m2] and chronic obstructive pulmonary disease); the area under the receiver operating characteristic curve (AUC) was 0.75 (95%CI 0.70-0.80). The risk of in-hospital death was 1.6-2.6 times higher in subjects with any of these risk factors (RFs), and increased by 2.6-6.0-fold in patients with any two RFs (versus no RFs). The mortality rate increased stepwise as the number of RFs increased (from 0.43% -none RF to 16.8%- ≥4RF). The prognostic value of a single RF was low (AUC ≤0.635) but combination of 2 or more RFs improved the prediction significantly; AUC reached 0.84(95%CI 0.77-0.90) when ≥4 RFs (versus 0-1RF) were present. In the validated and main cohorts the number of predicted by 1, 2, 3 or ≥4 RFs and observed deaths were practically similar. CONCLUSIONS: In HF patients, seven easily identifiable at admission characteristics, including 4 biomarkers, are strong and independent indicators of in-hospital mortality and can be used for risk stratification and individualised management.

Bone Turnover Status: Classification Model and Clinical Implications.

Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness. Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C-terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1±9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures. Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP>32 µg/L, bCTX≤0.250 µg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP ≤32 µg/L), normal bone resorption (bCTX≤0.250 µg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 µg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days. Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model.

Lower serum P1NP/ßCTX ratio and hypoalbuminemia are independently associated with osteoporotic nonvertebral fractures in older adults.

PURPOSE: To estimate the discriminative value of serum P1NP/ßCTX ratio and albumin levels in hospitalized orthogeriatric patients with and without nonvertebral fractures. METHODS: In 1,239 orthogeriatric patients (mean age 78.1±9.52 years, 69.1% women) including 854 (68.9%) with osteoporotic nonvertebral fractures (455 [36.7%] with hip fracture [HF]) and 385 (31.1%) without fractures, markers of bone formation (procollagen type 1 N-terminal propeptide [P1NP], osteocalcin [OC], and bone resorption (beta-C-terminal cross-linking telopeptide of type 1 collagen [ßCTX]), indices of mineral metabolism, and parameters of liver and renal functions were assessed; data on clinical and laboratory characteristics were collected prospectively. RESULTS: Both lower serum P1NP/ßCTX ratio and albumin concentration (as continuous or categorical variables) were independently associated with fracture presence in multivariate logistic regressions. Compared with the highest P1NP/ßCTX tertile, the prevalence of HF, after adjustment for multiple covariates, was 3-fold higher in the lowest tertile and 1.5 times higher in the middle tertile; presence of any fracture was 2.3- and 1.6-fold higher, respectively; patients with albumin levels in the lowest tertile had multivariate odds ratio (OR) of 4.6 for HF and 2.8 for any fracture, in the middle tertile the ORs were 2.2 and 1.3, respectively. The P1NP/ßCTX <100.0 (median) and hypoalbuminemia (<33 g/L) demonstrated area under the curve values for HF of 0.802 and 0.806, respectively, and for any fractures of 0.711 and 0.706, respectively. When both characteristics were combined, the ORs for HF or any fracture, compared with the nonfractured group, were 7.8 and 3.2, respectively, with an accuracy of 79.6% and 71.6%, respectively. CONCLUSIONS: In orthogeriatric patients, both serum P1NP/ßCTX ratio and albumin levels demonstrated an inverse dose-effect relationship with the prevalence of nonvertebral fractures and independently indicated fracture presence with acceptable discriminatory power. Lower P1NP/ßCTX (<100) and hypoalbuminemia could be useful simple additive prognostic tools for fracture risk stratification in the elderly.

Facebook advertising for participant recruitment into a blood pressure clinical trial.

OBJECTIVES: Recruitment of sufficient sample size into clinical trials is challenging. Conventional advertising methods are expensive and are often ineffective. The effectiveness of Facebook for recruitment into blood pressure clinical trials of middle-to-older-aged people is unknown. This study aimed to assess this by comparing Facebook advertising with conventional recruitment methods from a retrospective analysis within a clinical trial. METHODS: Conventional advertisements (newspaper, radio and posters) were employed for the first 20 months of a randomized controlled clinical trial conducted in three Australian capital cities from Tasmania, Queensland and the Australian Capital Territory. With dwindling participant recruitment, at 20 months a Facebook advertising campaign was employed intermittently over a 4-month period. Recruitment results were retrospectively compared with those using conventional methods in the previous 4 months. RESULTS: Compared with conventional recruitment methods, Facebook advertisement was associated with a significant increase in the number of participants recruited in the Australian Capital Territory (from an average 1.8-7.3/month; P < 0.05). There was also an increase in Tasmania that was of borderline significance (from 4.0 participants recruited/month to 9.3/month; P = 0.052). However, there was no effect in Queensland (from 6.0 participants recruited/month to 3.0/month; P = 0.15). Facebook advertisement was associated with a significant decrease in the age of participants enquiring into the study (from 60.9 to 58.7 years; P < 0.001). CONCLUSION: Facebook advertising was successful in helping to increase recruitment of middle-to-older aged participants into a blood pressure clinical trial, although there may be some variability in effect that is dependent on location.

The Neutrophil to Lymphocyte Ratio on Admission and Short-Term Outcomes in Orthogeriatric Patients.

AIM: To investigate the association of the neutrophil to lymphocyte ratio (NLR) at admission with presence of fracture, comorbid conditions, and its prognostic value for short-term outcomes in orthogeriatric patients. METHODS: On 415 consecutive patients (mean age 78.8 ±8.7[SD] years, 281 women, 255 with a non-vertebral bone fracture, including 167 with a hip fracture, HF) admitted to the Department of Orthopaedic Surgery at the Canberra hospital (2010 - 2011) data on clinical and laboratory characteristics were collected prospectively. The validation dataset included 294 consecutive patients (mean age 82.1 ± 8.0 years, 72.1% women) with HF. RESULTS: Multivariate regression revealed four variables, presence of HF, hypoalbuminaemia (<33g/L), anaemia (<120g/L) and hyperparathyroidism (PTH>6.8 pmol/L), as independent determinants of admission NLR≥5.1. There was a dose-graded relationship between presence of fracture, especially HF, postoperative complications and levels of NLR categorized as tertiles. Compared to patients with NLR<5.1(first tertile), patients with NLR 5.1-8.5 (second tertile) had a 1.8-, 3.1-, 2.6-, and 2.5-fold higher risk for presence of any fracture, HF, developing postoperative myocardial injury (troponin I rise) and a high inflammatory response/infection (CRP>100mg/L after the 3rd postoperative day), respectively, while in subjects with NLR>8.5 (third tertile) these risks were 2.6-, 4.9-, 5.9- and 4.5-times higher, respectively; subjects with NLR>8.5 had a 9.7 times higher chance of dying in the hospital compared to patients with NLR 5.1-8.5; the NLR retained its significance on multivariate analyses. The NLR ≥5.1 predicted postoperative myocardial injury with an area under the curve (AUC) of 0.626, CRP>100mg/L with AUC of 0.631 and the NLR >8.5 predicted in-hospital mortality with an AUC of 0.793, showing moderately high sensitivity (86.7%, 80% and 90%, respectively) and negative predictive value (92.9%, 71.2%, 99.6%, respectively), but low specificity. Admission NLR was superior to other, except hypoalbuminaemia, prognostic markers; combined use of both NLR≥5.1 and albumin<33g/L only moderately increased the accuracy of prediction. The validation study confirmed the prognostic value of the admission NLR. CONCLUSIONS: In orthogeriatric patients, high NLR on admission is an independent indicator of fracture presence, a significant risk factor and moderate predictor of postoperative myocardial injury, high inflammatory response/infection and in-hospital death.

Liver function parameters in hip fracture patients: relations to age, adipokines, comorbidities and outcomes.

AIM: To asses liver markers in older patients with hip fracture (HF) in relation to age, comorbidities, metabolic characteristics and short-term outcomes. METHODS: In 294 patients with HF (mean age 82.0±7.9 years, 72.1% women) serum alanine aminotransferase (ALT), gammaglutamyltransferase (GGT), alkaline phosphatase (ALP), albumin, bilirubin, 25(OH)vitaminD, PTH, calcium, phosphate, magnesium, adiponectin, leptin, resistin, thyroid function and cardiac troponin I were measured. RESULTS: Elevated ALT, GGT, ALP or bilirubin levels on admission were observed in 1.7%-9.9% of patients. With age GGT, ALT and leptin decrease, while PTH and adiponectin concentrations increase. Higher GGT (>30 U/L, median level) was associated with coronary artery disease (CAD), diabetes mellitus (DM), and alcohol overuse; lower ALT (≤20 U/L, median level) with dementia; total bilirubin>20 µmol/L with CAD and alcohol overuse; and albumin>33 g/L with CAD. Multivariate adjusted regression analyses revealed ALT, ALP, adiponectin, alcohol overuse and DM as independent and significant determinants of GGT (as continuous or categorical variable); GGT for each other liver marker; and PTH for adiponectin. The risk of prolonged hospital stay (>20 days) was about two times higher in patients with GGT>30 U/L or adiponectin>17.14 ng/L (median level) and 4.7 times higher if both conditions coexisted. The risk of in-hospital death was 3 times higher if albumin was <33 g/L. CONCLUSIONS: In older HF patients liver markers even within the normal range are associated with age-related disorders and outcomes. Adiponectin (but not 25(OH)vitaminD, PTH, leptin or resistin) is an independent contributor to higher GGT. Serum GGT and albumin predict prolonged hospital stay and in-hospital death, respectively. A unifying hypothesis of the findings presented.

Trends in stroke survival incidence rates in older Australians in the new millennium and forecasts into the future.

AIMS: The objective of this study is (i) to evaluate trends in the incidence rates of stroke survivors aged 60 years and older over a 11-year period in the Australian Capital Territory (ACT) and (ii) to forecast future trends in Australia until 2051. METHODS: Analysis of age- and sex-specific standardized incidence rates of older first-ever stroke survivors in ACT from 1999-2000 to 2009-2010 and projections of number of stroke survivors (NSS) in 2021 and 2051 using 2 models based only on (i) demographic changes and (ii) assuming changing of both incidence rates and demography. RESULTS: In the ACT in the first decade of the 21st century, the absolute numbers and age-adjusted standardized incidence rates of stroke survivors (measured as a function of age and period) increased among both men and women aged 60 years or older. The trend toward increased survival rates in both sexes was driven mainly by population aging, whereas the effect of stroke year was more pronounced in men compared with women. The absolute NSS (and the financial burden to the society) in Australia is predicted to increase by 35.5%-59.3% in 2021 compared with 2011 and by 1.6- to 4.6-fold in 2051 if current only demographic (first number) or both demographic and incidence trends (second number) continue. CONCLUSIONS: Our study demonstrates favorable trends in stroke survivor rates in Australia in the first decade of the new millennium and projects in the foreseeable future significant increases in the absolute numbers of older stroke survivors, especially among those aged 70 years or older and men.

Poststroke hip fracture: prevalence, clinical characteristics, mineral-bone metabolism, outcomes, and gaps in prevention.

Objective. To assess the prevalence, clinical and laboratory characteristics, and short-term outcomes of poststroke hip fracture (HF). Methods. A cross-sectional study of 761 consecutive patients aged ≥60 years (82.3 ± 8.8 years; 75% females) with osteoporotic HF. Results. The prevalence of poststroke HF was 13.1% occurring on average 2.4 years after the stroke. The poststroke group compared to the rest of the cohort had a higher proportion of women, subjects with dementia, history of TIA, hypertension, coronary artery disease, secondary hyperparathyroidism, higher serum vitamin B12 levels (>350 pmol/L), walking aid users, and living in residential care facilities. The majority of poststroke HF patients had vitamin D insufficiency (68%) and excess bone resorption (90%). This group had a 3-fold higher incidence of postoperative myocardial injury and need for institutionalisation. In multivariate analysis, independent indicators of poststroke HF were female sex (OR 3.6), history of TIA (OR 5.2), dementia (OR 4.1), hypertension (OR 3.2), use of walking aid (OR 2.5), and higher vitamin B12 level (OR 2.3). Only 15% of poststroke patients received antiosteoporotic therapy prior to HF. Conclusions. Approximately one in seven HFs occurs in older stroke survivors and are associated with poorer outcomes. Early implementation of fracture prevention strategies is needed.

Directional migration of recirculating lymphocytes through lymph nodes via random walks.

Naive T lymphocytes exhibit extensive antigen-independent recirculation between blood and lymph nodes, where they may encounter dendritic cells carrying cognate antigen. We examine how long different T cells may spend in an individual lymph node by examining data from long term cannulation of blood and efferent lymphatics of a single lymph node in the sheep. We determine empirically the distribution of transit times of migrating T cells by applying the Least Absolute Shrinkage & Selection Operator (LASSO) or regularised S-LASSO to fit experimental data describing the proportion of labelled infused cells in blood and efferent lymphatics over time. The optimal inferred solution reveals a distribution with high variance and strong skew. The mode transit time is typically between 10 and 20 hours, but a significant number of cells spend more than 70 hours before exiting. We complement the empirical machine learning based approach by modelling lymphocyte passage through the lymph node insilico. On the basis of previous two photon analysis of lymphocyte movement, we optimised distributions which describe the transit times (first passage times) of discrete one dimensional and continuous (Brownian) three dimensional random walks with drift. The optimal fit is obtained when drift is small, i.e. the ratio of probabilities of migrating forward and backward within the node is close to one. These distributions are qualitatively similar to the inferred empirical distribution, with high variance and strong skew. In contrast, an optimised normal distribution of transit times (symmetrical around mean) fitted the data poorly. The results demonstrate that the rapid recirculation of lymphocytes observed at a macro level is compatible with predominantly randomised movement within lymph nodes, and significant probabilities of long transit times. We discuss how this pattern of migration may contribute to facilitating interactions between low frequency T cells and antigen presenting cells carrying cognate antigen.

Interactions between Serum Adipokines and Osteocalcin in Older Patients with Hip Fracture.

Introduction. Experiments on genetically modified animals have discovered a complex cross-regulation between adipokines (leptin, adiponectin) and osteocalcin. The relationships between these molecules in human osteoporosis are still unclear. We evaluated the hypothesis of a bidirectional link between adipokines and osteocalcin. Materials and Methods. In a cross-sectional study of 294 older patients with osteoporotic hip fracture, we estimated serum concentrations of leptin, adiponectin, resistin, osteocalcin, parameters of mineral metabolism, and renal function. Results. After adjustment for multiple potential confounders, serum osteocalcin concentration was inversely associated with resistin and positively with leptin, leptin/resistin ratio, and adiponectin/resistin ratio. In multivariate regression models, osteocalcin was an independent predictor of serum leptin, resistin, leptin/resistin, and adiponectin/resistin ratios. Conclusions. Our data support the bidirectional regulation between osteocalcin and adipokines, but contrary to the genetically modified animal models, in older subjects with osteoporotic hip fracture, serum osteocalcin is positively associated with leptin and inversely with resistin.

Clinical profiles and risk factors for outcomes in older patients with cervical and trochanteric hip fracture: similarities and differences.

BACKGROUND: Data on clinical characteristics and outcomes in regard to hip fracture (HF) type are controversial. This study aimed to evaluate whether clinical and laboratory predictors of poorer outcomes differ by HF type. METHODS: Prospective evaluation of 761 consecutively admitted patients (mean age 82.3 ± 8.8 years; 74.9% women) with low-trauma non-pathological HF. Clinical characteristics and short-term outcomes were recorded. Haematological, renal, liver and thyroid status, C-reactive protein, cardiac troponin I, serum 25(OH) vitamin D, PTH, leptin, adiponectin and resistin were determined. RESULTS: The cervical compared to the tronchanteric HF group was younger, have higher mean haemoglobin, albumin, adiponectin and resistin and lower PTH levels (all P < 0.05). In-hospital mortality, length of hospital stay (LOS), incidence of post-operative myocardial injury and need of institutionalisation were similar in both groups. Multivariate analysis revealed as independent predictors for in-hospital death in patient with cervical HF male sex, hyperparathyroidism and lower leptin levels, while in patients with trochanteric HF only hyperparathyroidism; for post-operative myocardial injury dementia, smoking and renal impairment in the former group and coronary artery disease (CAD), hyperparathyroidism and hypoleptinaemia in the latter; for LOS > 20 days CAD, and age > 75 years and hyperparathyroidism, respectively. Need of institutionalisation was predicted by age > 75 years and dementia in both groups and also by hypovitaminosis D in the cervical and by hyperparathyroidism in the trochanteric HF. CONCLUSIONS: Clinical characteristics and incidence of poorer short-term outcomes in the two main HF types are rather similar but risk factors for certain outcomes are site-specific reflecting differences in underlying mechanisms.

Hip fracture type: important role of parathyroid hormone (PTH) response to hypovitaminosis D.

OBJECTIVE: To investigate whether clinical and laboratory characteristics, including serum 25-hydroxyvitamin D (25(OH) D), PTH and parameters of mineral and bone metabolism, differ by hip fracture (HF) type. PATIENTS AND METHODS: We studied prospectively 761 consecutively admitted older patients (mean age 82.3+8.8(SD) years; 74.9% women) with low trauma non-pathological HF. A detailed clinical examination was performed, haematologic, renal, liver and thyroid function tests, serum 25(OH)D, PTH, calcium, phosphate, magnesium, C-reactive protein (CRP) and cardiac troponin I (cTnI) measured. In a subset of 294 patients' markers of bone formation (serum osteocalcin, OC; bone specific alkaline phosphatase, BAP) and bone resorption (urinary deoxypyridinoline, DPD/Cr; N-terminal cross-linked telopeptide of type 1 collagen, NTx/Cr; both corrected to urinary creatinine, Cr) were also measured. RESULTS: In the trochanteric compared to the cervical group, females were older than males and the prevalence of Parkinson's disease, mean haemoglobin and albumin levels were lower. Incidence and degree of myocardial injury (cTnl rise) and inflammatory reaction (CRP elevation) as well as length of hospital stay, need of institutionalisation or in-hospital mortality were similar in both groups. Hypovitaminosis D (25(OH)D <50 mmol/L) was present in 77.8% of patients with cervical and in 82.1% with trochanteric HF, elevated PTH (>6.8 pmol/L) in 30.2% and 41.3%, respectively. The associations between 25(OH)D, PTH, and parameters of mineral metabolism and bone turnover were site-specific. In multivariate analyses, PTH (both as a continuous or categorical variable) response to hypovitaminosis D was a strong independent predictor of HF type. Coexistence of vitamin D deficiency (25(OH) D< 25 nmol/L) and elevated PTH predicts trochanteric HF while blunted PTH response predicts cervical HF (OR=3.5; 95% CI 1.5-80; p=0.005). PTH response and phosphate status (above or below median level) correctly discriminated HF type in 73.8% of patients with vitamin D deficiency. CONCLUSIONS: HF type is significantly associated with PTH response to hypovitaminosis D and impaired phosphate homeostasis. We detected only minor differences between two main HF types with regard to a wide range of clinical and routine laboratory variables as well as short-term outcomes.

Bisphosphonate use and hip fracture epidemiology: ecologic proof from the contrary.

AIM: The objective of this article is to evaluate the relationship between the changes in prescriptions of antiosteoporotic drugs (mainly the rapid fall in the use of bisphosphonates [BPs]) and standardized hip fracture (HF) rates over the period 2005-2008 in the Australian Capital Territory (ACT). METHODS: Annual sex- and age-specific HF rates (per 100,000 population) were determined and standardized using the Australian 2006 population census. Data on the annual prescriptions of BPs (mainly alendronate and risedronate), strontium ranelate, and hormone replacement therapy were obtained from the Australian Pharmaceutical Benefits Scheme (PBS) and Repatriation Australian Pharmaceutical Benefits Scheme (RPBS) databases. RESULTS: In the ACT, the peak annual number of prescriptions for BPs was observed in 2006. Following reports linking osteonecrosis of the jaw with BP use, the number of BP prescriptions dropped by 14% in 2007-2008 compared with 2005, when the lowest HF rates were recorded. The reduction in BP prescriptions coincided with increased HF rates in females in 2007 (+22.6%) and in 2008 (+25.2%) compared with 2005; in males, HF incidence declined by 6.6% and 16.7%, respectively. The proportion of filled prescriptions for strontium ranelate, risedronate, and alendronate in 2007-2008 was 1:8.4:15.5, indicating that BPs were the dominant antiosteoporotic drugs. There was an inverse statistically significant relationship between the total annual number of BP prescriptions and standardized HF incidence rates for the 10-year period 1999-2008. CONCLUSION: Although currently there is no clear understanding of factors contributing to changing HF epidemiology, the available evidence suggests that much of the decline in HF rates is due to the use of BPs. The fall in the use of BPs is associated with an increase in HF rates in females, indicating that BPs should still be considered the first-line medications for the prevention and treatment of osteoporosis. Our results need to be confirmed in other populations and countries.

Influence of adiposity and physical activity on arterial stiffness in healthy children: the lifestyle of our kids study.

Childhood obesity is increasingly prevalent in the community and is related to adverse cardiovascular outcomes during adulthood. In this study of healthy children, we evaluated the influence of adiposity and physical activity on carotid-femoral pulse wave velocity (PWV), an index of arterial stiffness and a marker of cardiovascular risk in adults. In 573 community-based children (mean age: 10.1+/-0.3 years; 51% boys), we measured body mass index and waist circumference. Percentage body fat was quantitated by dual-energy x-ray absorptiometry. Cardiorespiratory fitness (CRF) and physical activity levels were assessed using a 20-m shuttle run and 7-day pedometer count, respectively. PWV was estimated by applanation tonometry. In univariate analysis, PWV was positively correlated with body mass index (r=0.34), waist circumference (r=0.32), and percentage body fat (r=0.32; P<0.001 for all) and negatively correlated with CRF (r=-0.23; P<0.001) and pedometer count (r=-0.08; P=0.046). In separate multivariable linear regression models, body mass index, waist circumference, and percentage of body fat were independently and positively associated with PWV (P<0.01 for all) after adjusting for age, sex, systolic blood pressure, mean arterial pressure, heart rate, and CRF (P<0.01 for all). The influence of CRF on PWV was attenuated after adjusting for adiposity. In conclusion, increased body mass and adiposity and decreased CRF are associated with arterial stiffening in healthy prepubescent children.

The lifestyle of our kids (LOOK) project: outline of methods.

This methods paper outlines the overall design of a community-based multidisciplinary longitudinal study with the intent to stimulate interest and communication from scientists and practitioners studying the role of physical activity in preventive medicine. In adults, lack of regular exercise is a major risk factor in the development of chronic degenerative diseases and is a major contributor to obesity, and now we have evidence that many of our children are not sufficiently active to prevent early symptoms of chronic disease. The lifestyle of our kids (LOOK) study investigates how early physical activity contributes to health and development, utilizing a longitudinal design and a cohort of eight hundred and thirty 7-8-year-old (grade 2) school children followed to age 11-12 years (grade 6), their average family income being very close to that of Australia. We will test two hypotheses, that (a) the quantity and quality of physical activity undertaken by primary school children will influence their psychological and physical health and development; (b) compared with existing practices in primary schools, a physical education program administered by visiting specialists will enhance health and development, and lead to a more positive perception of physical activity. To test the first hypothesis we will monitor all children longitudinally over the 4 years. To test the second we will involve an intervention group of 430 children who receive two 50min physical education classes every week from visiting specialists and a control group of 400 who continue with their usual primary school physical education with their class-room teachers. At the end of grades 2, 4, and 6 we will measure several areas of health and development including blood risk factors for chronic disease, cardiovascular structure and function, physical fitness, psychological characteristics and perceptions of physical activity, bone structure and strength, motor control, body composition, nutritional intake, influence of teachers and family, and academic performance.

Aortic stiffness for the detection of preclinical left ventricular diastolic dysfunction: pulse wave velocity versus pulse pressure.

OBJECTIVE: An age-dependent relationship between aortic and left ventricular (LV) stiffening has been observed in community-based adults. Our aim was to compare the performances of wave reflection-dependent (pulse pressure) and independent [carotid-femoral pulse wave velocity (PWV)] indexes of aortic stiffness to detect preclinical LV diastolic dysfunction. METHODS: In this case-control study, a stratified subsample of participants of a population-based echocardiographic survey with LV ejection fraction higher than 45% and without overt heart failure was randomly selected to undergo assessment of brachial blood pressure, LV diastolic function by Doppler echocardiography, and estimation of central aortic pressures and PWV by applanation tonometry. RESULTS: Of the 233 subjects (mean age 73 +/- 6 years, 54% men), 84 had normal diastolic function, 99 had mild diastolic dysfunction, and 50 had moderate or severe diastolic dysfunction. Brachial pulse pressure, central pulse pressure, and PWV progressively increased according to the severity of diastolic dysfunction, independent of age and sex. The overall performance of PWV was superior to brachial pulse pressure [area under receiver operating characteristic curve (AUC): 0.70 versus 0.59, respectively; P = 0.005] and central pulse pressure (AUC: 0.70 versus 0.56, respectively; P = 0.001) for the detection of any diastolic dysfunction. CONCLUSION: PWV appeared to be superior to central and brachial pulse pressure for the detection of diastolic dysfunction in older adults with 'preserved' LV ejection fraction.