A Frailty Index predicts 10-year fracture risk in adults age 25 years and older: results from the Canadian Multicentre Osteoporosis Study (CaMos).

UNLABELLED: We created a 30-item Frailty Index in the Canadian Multicentre Osteoporosis Study. A Frailty Index is a sensitive measure that can quantify fracture risk according to degree of frailty. Our results indicated that at any age, frailty was an important independent risk factor for fracture over 10 years. INTRODUCTION: In later life, frailty has been linked to fractures. It is likely that the antecedents of fracture are seen across the life course, in ways not entirely captured by traditional osteoporosis risk factors. Using data collected from the prospective, population-based Canadian Multicentre Osteoporosis Study (CaMos), we created the 30-item CaMos Frailty Index and examined whether it was associated with incident fractures over 10 years. METHODS: All CaMos participants aged 25 years and older (n = 9,423) were included in the analysis. To examine the relationship between baseline Frailty Index scores and incident fractures, a competing risk proportional sub-distribution hazards model was used with death considered a competing risk. Analyses were adjusted for age, sex, body mass index, education level, femoral neck T-score, and antiresorptive therapy. RESULTS: At baseline, the mean age was 62.1 years [standard deviation (SD) 13.4], and 69.4 % were women. The mean Frailty Index score was 0.13 (SD 0.11), ranging from 0 to 0.66. For every 0.10 increase in Frailty Index scores (approximately one SD), the hazard ratio was 1.25 (p < 0.001) for all fractures, 1.18 (p = 0.043) for hip fractures, and 1.30 (p ≤ 0.001) for clinical vertebral fractures. CONCLUSION: The CaMos Frailty Index quantified fracture risk according to degree of frailty. Irrespective of age and bone mineral density, the Frailty Index was associated with hip, vertebral, and all-type clinical fractures. Predicting late onset illnesses may have to consider overall health status and not just traditional risk factors.

Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS).

UNLABELLED: We used data from a large, prospective Canadian cohort to assess the association between selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) and fracture. We found an increased risk of fractures in individuals who used SSRI or SNRI, even after controlling for multiple risk factors. INTRODUCTION: Previous studies have suggested an association between SSRIs and increasing risk of fragility fractures. However, the majority of these studies were not long-term analyses or were performed using administrative data and, thus, could not fully control for potential confounders. We sought to determine whether the use of SSRIs and SNRIs is associated with increased risk of fragility fracture, in adults aged 50 + . METHODS: We used data from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective randomly selected population-based community cohort; our analyses focused on subjects aged 50+. Time to event methodology was used to assess the association between SSRI/SNRI use, modeled time-dependently, and fragility fracture. RESULTS: Among 6,645 subjects, 192 (2.9%) were using SSRIs or/and SNRIs at baseline. During the 10-year study period, 978 (14.7%) participants experienced at least one fragility fracture. In our main analysis, SSRI/SNRI use was associated with increased risk of fragility fracture (hazard ratio (HR), 1.88; 95% confidence intervals (CI), 1.48-2.39). After controlling for multiple risk factors, including Charlson score, previous falls, and bone mineral density hip and lumbar bone density, the adjusted HR for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32-2.14). CONCLUSIONS: Our results lend additional support to an association between SSRI/SNRI use and fragility fractures. Given the high prevalence of antidepressants use, and the impact of fractures on health, our findings may have a significant clinical impact.

Peripheral quantitative computed tomography-derived muscle density and peripheral magnetic resonance imaging-derived muscle adiposity: precision and associations with fragility fractures in women.

PURPOSE: To determine the degree to which muscle density and fractures are explained by inter and intramuscular fat (IMF). METHODS: Women ⋝50 years of age (Hamilton, ON, Canada) had peripheral magnetic resonance imaging and peripheral quantitative computed tomography scans at 66% of the tibial length. Muscle on computed tomography images was segmented from subcutaneous fat and bone using fixed thresholds, computing muscle density. IMF was segmented from muscle within magnetic resonance images using a region-growing algorithm, computing IMF volume. Fracture history over the last 14 years was obtained. Odds ratios for fractures were determined for muscle density, adjusting for IMF volume, total hip BMD, age and body mass index. RESULTS: Women with a history of fractures were older (N=32, age:75.6±8.3 years) than those without (N=39, age: 67.0±5.2 years) (<0.01). IMF volume explained 49.3% of variance in muscle density (p<0.001). Odds for fractures were associated with lower muscle density even after adjusting for IMF volume but were attenuated after adjusting for age. CONCLUSIONS: Muscle adiposity represents only 50% of the muscle density measurement. Properties of muscle beyond its adiposity may be related to fractures, but larger and prospective studies are needed to confirm these associations.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Fragility fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study.

UNLABELLED: Canadian women over 50 years old were studied over a 10-year period to see if those who sustained a fracture (caused by minimal trauma) were receiving the recommended osteoporosis therapy. We found that approximately half of these women were not being treated, indicating a significant care gap in osteoporosis treatment. INTRODUCTION: Prevalent fragility fracture strongly predicts future fracture. Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment. We aimed to describe post fracture care in Canadian women using a large, population-based prospective cohort that began in 1995-1997. METHODS: We followed 5,566 women over 50 years of age from across Canada over a period of 10 years in the Canadian Multicentre Osteoporosis Study. Information on medication use and incident clinical fragility fractures was obtained during a yearly questionnaire or interview and fractures were confirmed by radiographic/medical reports. RESULTS: Over the 10-year study period, 42-56% of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication. During year 1 of the study, 22% of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26% were on hormone therapy (HT). We were not able to differentiate HT use for menopause symptoms vs osteoporosis. Use of bisphosphonate therapy increased over time; odds ratio (OR) for use at year 10 compared to use at year 1 was 3.65 (95% confidence interval (CI) 1.83-7.26). In contrast, HT use declined, with an OR of 0.07 (95%CI 0.02-0.24) at year 10 compared to year 1 of the study. CONCLUSION: In a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures. Although bisphosphonate therapy usage improved over time, a substantial gap remains.

The impact of incident fractures on health-related quality of life: 5 years of data from the Canadian Multicentre Osteoporosis Study.

UNLABELLED: Using prospective data from the Canadian Multicentre Osteoporosis Study (CaMos), we compared health utilities index (HUI) scores after 5 years of follow-up among participants (50 years and older) with and without incident clinical fractures. Incident fractures had a negative impact on HUI scores over time. INTRODUCTION: This study examined change in health-related quality of life (HRQL) in those with and without incident clinical fractures as measured by the HUI. METHODS: The study cohort was 4,820 women and 1,783 men (50 years and older) from the CaMos. The HUI was administered at baseline and year 5. Participants were sub-divided into incident fracture groups (hip, rib, spine, forearm, pelvis, other) and were compared with those without these fractures. The effects of both time and fracture type on HUI scores were examined in multivariable regression analyses. RESULTS: Men and women with hip fractures, compared to those without, had lower HUI measures that ranged from -0.05 to -0.25. Both women and men with spine fractures had significant deficits on the pain attributes (-0.07 to -0.12). In women, self-care (-0.06), mobility and ambulation (-0.05) were also negatively impacted. Women with rib fractures had deficits similar to women with spine fractures, and these effects persisted over time. In men, rib fractures did not significantly affect HUI scores. Pelvic and forearm fractures did not substantially influence HUI scores. CONCLUSION: The HUI was a sensitive measure of HRQL change over time. These results will inform economic analyses evaluating osteoporosis therapies.

The Tough Guy prehospital experience: patterns of injury at a major UK endurance event.

BACKGROUND: Data from mass gathering events help when planning allocation of resources and in setting standards of care. There is currently a lack of data from the UK. AIM: To determine the frequency of injuries and hospital transfer rates at a large outdoor endurance event. METHODS: 251 patient attendances from four consecutive events over 2 years (two summers two winters; 2006-2007) were analysed. RESULTS: 1%-2% of contenders required medical help. Hypothermia (n = 84), soft tissue problems (n = 71) and musculoskeletal problems (n = 51) were the most common conditions encountered. 4% of patients required immediate transfer to the hospital. The medical team was able to prevent 31 hospital transfers, which represents a reduction of 78%. 13% of cases specifically required a doctor who was able to prevent more immediate hospital transfers than other care givers. The majority of injuries were classified as minor (n = 228), with the remaining as intermediate (n = 23); there were no life-threatening injuries or deaths. No patient required intravenous fluid. Overall, in winter, more patients were treated when compared with summer (157 vs 94). There were significantly more retirements in winter (69 vs 22, p<0.001), although hospital transfer rates were similar. CONCLUSIONS: Medical teams should plan for casualty rates of 1%-2% of competitors and hospital transfer rates of approximately 5% of patients treated. Outdoor events in winter create more casualties than in summer and require greater resources. Trauma and exposure injuries are common; critical illness is uncommon. An adequately equipped and skilled medical team reduces hospital admissions.

Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism.

Here, we show that disruption of N-ethylmaleimide-sensitive fusion protein- (NSF-) GluR2 interaction by infusion into cultured hippocampal neurons of a blocking peptide (pep2m) caused a rapid decrease in the frequency but no change in the amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). N-methyl-D-aspartate (NMDA) receptor-mediated mEPSCs were not changed. Viral expression of pep2m reduced the surface expression of alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptors, whereas NMDA receptor surface expression in the same living cells was unchanged. In permeabilized neurons, the total amount of GluR2 immunoreactivity was unchanged, and a punctate distribution of GluR2 was observed throughout the dendritic tree. These data suggest that the NSF-GluR2 interaction is required for the surface expression of GluR2-containing AMPA receptors and that disruption of the interaction leads to the functional elimination of AMPA receptors at synapses.

Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons.

AMPA and NMDA receptors mediate most excitatory synaptic transmission in the CNS. We have developed antibodies that recognize all AMPA or all NMDA receptor variants on the surface of living neurons. AMPA receptor variants were identified with a polyclonal antibody recognizing the conserved extracellular loop region of all four AMPA receptor subunits (GluR1-4, both flip and flop), whereas NMDA receptors were immunolabeled with a polyclonal antibody that binds to an extracellular N-terminal epitope of the NR1 subunit, common to all splice variants. In non-fixed brain sections these antibodies gave labeling patterns similar to autoradiographic distributions with particularly high levels in the hippocampus. Using these antibodies, in conjunction with GluR2-specific and synaptophysin antibodies, we have directly localized and quantified surface-expressed native AMPA and NMDA receptors on cultured living hippocampal neurons during development. Using a quantitative cell ELISA, a dramatic increase was observed in the surface expression of AMPA receptors, but not NMDA receptors, between 3 and 10 d in culture. Immunocytochemical analysis of hippocampal neurons between 3 and 20 d in vitro shows no change in the proportion of synapses expressing NMDA receptors (approximately 60%) but a dramatic increase (approximately 50%) in the proportion of them that also express AMPA receptors. Furthermore, over this period the proportion of AMPA receptor-positive synapses expressing the GluR2 subunit increased from approximately 67 to approximately 96%. These changes will dramatically alter the functional properties of hippocampal synapses.

Effectiveness and efficiency of selective vs universal screening for chlamydial infection in sexually active young women.

BACKGROUND: Since chlamydial cervicitis is not associated with specific complaints, screening asymptomatic women is an important initiative to prevent pelvic inflammatory disease and its sequelae. Compared with universal screening, selective screening is less costly but less effective so the cost savings vs the consequences of missing infected women need to be weighed carefully. METHODS: In two family planning clinics, 1002 women were surveyed for chlamydial infection (prevalence, 7%) and its predictors to determine whether universal or selective screening is the most efficient strategy. Two rules for the selection of patients were determined by logistic regression modeling and their relative efficiencies were compared by incremental cost-effectiveness and sensitivity analysis. The validity of the screening rules was tested in 191 students attending a university health clinic. RESULTS: If those with cervical friability, suspicious discharge, urinary frequency, or intermenstrual bleeding had been tested, 55.3% of all women would have been screened and 83.3% of all cases would have been detected. If those reporting a new sex partner in the preceding year had also been tested, 75.4% would have been screened, identifying 93.3% of all cases. The predictive power and practicality of the selection rules were validated in the university health clinic sample. Sensitivity analyses showed selective screening using cervical enzyme immunoassay with blocking confirmation was efficient if the prevalence of chlamydial infection was 16% or less, 11% or less, or 5% or less depending on whether base analyses, overestimated costs, or worst performance scenarios, respectively, were used. CONCLUSIONS: Selective screening based on four or five predictors and confirmed cervical enzyme immunoassay is an effective and efficient strategy in low prevalence settings.

Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian Multicentre Osteoporosis Study.

This cross-sectional cohort study of 5566 women and 2187 men 50 years of age and older in the population-based Canadian Multicentre Osteoporosis Study was conducted to determine whether reported past diseases are associated with bone mineral density or prevalent vertebral deformities. We examined 12 self-reported disease conditions including diabetes mellitus (types 1 or 2), nephrolithiasis, hypertension, heart attack, rheumatoid arthritis, thyroid disease, breast cancer, inflammatory bowel disease, neuromuscular disease, Paget's disease, and chronic obstructive pulmonary disease. Multivariate linear and logistic regression analyses were performed to determine whether there were associations among these disease conditions and bone mineral density of the lumbar spine, femoral neck, and trochanter, as well as prevalent vertebral deformities. Bone mineral density measurements were higher in women and men with type 2 diabetes compared with those without after appropriate adjustments. The differences were most notable at the lumbar spine (+0.053 g/cm2), femoral neck (+0.028 g/cm2), and trochanter (+0.025 g/cm2) in women, and at the femoral neck (+0.025 g/cm2) in men. Hypertension was also associated with higher bone mineral density measurements for both women and men. The differences were most pronounced at the lumbar spine (+0.022 g/cm2) and femoral neck (+0.007 g/cm2) in women and at the lumbar spine (+0.028 g/cm2) in men. Although results were statistically inconclusive, men reporting versus not reporting past nephrolithiasis appeared to have clinically relevant lower bone mineral density values. Bone mineral density differences were -0.022, -0.015, and -0.016 g/cm2 at the lumbar spine, femoral neck, and trochanter, respectively. Disease conditions were not strongly associated with vertebral deformities. In summary, these cross-sectional population-based data show that type 2 diabetes and hypertension are associated with higher bone mineral density in women and men, and nephrolithiasis may be associated with lower bone mineral density in men. The importance of these associations for osteoporosis case finding and management require further and prospective studies.

An electrophysiological characterisation of long-term potentiation in cultured dissociated hippocampal neurones.

Long-term potentiation (LTP) of synaptic transmission is under intense investigation. It is believed that the mechanisms involved in its induction and expression are critically involved in synaptic processes that are important for learning and memory and other physiological functions. A reliable means of inducing LTP in dissociated cultured neurones would facilitate investigations into the molecular basis of LTP but has been hard to achieve. Here we report a mechanism for inducing LTP in postnatal dissociated hippocampal neurones using transient depolarisation. This form of LTP is prevented by NMDA receptor antagonists and by chelating Ca2+ in the postsynaptic neurone. It is manifest primarily as an increase in the frequency of mEPSCs.

Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes.

The molecular mechanisms underlying long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus are not well understood. Transient depolarisation of cultured postnatal hippocampal neurones (3x1 s exposure to 90 mM K+) induces a form of LTP that is manifest primarily as an increase in mEPSC frequency. Site-directed antibodies that recognise an extracellular region of all AMPA receptor (AMPAR) subunits (GluR1-4) were used for the immunolabelling of living neurones. These antibodies were raised in two species to enable sequential immunofluorescent labelling of individual living neurones before and after the induction of LTP. High K+ treatment resulted in the appearance of new AMPAR clusters at sites on the neuronal surface that previously lacked detectable AMPARs. The appearance of new AMPAR clusters was NMDA receptor (NMDAR)-dependent since it was antagonised by the application of NMDAR antagonists. Our data indicate that the transient synaptic activation of NMDARs can lead to the insertion of native AMPARs at sites on the neuronal membrane that initially lacks AMPARs.

The natural history of bronchial atresia. Serial observations of a case from birth to operative correction.

A 10-year-old child presented with a history of intermittent respiratory symptoms since birth. Progressive shift of the mediastinum away from a hyperexpanded left upper lobe to the right side was evident on serial chest films, since birth. Bronchograms demonstrated atresia of the bronchus to the hyperexpanded segment. Xenon washout demonstrated prolonged half-time in the left upper lobe resulting from collateral ventilatory channels. Resection of the apical posterior segment of the left upper lobe was performed without complication. Bronchial atresia with collateral ventilation caused "lobar emphysema" in this patient.

Clamp/repair: a safe technique for treatment of blunt injury to the descending thoracic aorta.

Debate exists with regard to the use of pump bypass, shunt bypass, or clamp/repair techniques in treating injuries to the descending thoracic aorta. The objective in using any of these techniques is to minimize the complications of paraplegia and renal failure, while achieving the lowest possible mortality. During an eighteen-year period, 45 patients were seen with acute blunt injury to the descending thoracic aorta. The shunt bypass method of repair was used in 1; pump bypass in 8; and clamp/repair in 23. There were desperate unsuccessful attempts to resuscitate and control hemorrhage in 13 patients, 1 of whom was placed on portable pump bypass. Thirty-two patients survived resuscitation and operation, and 26 were long-term survivors. Among surviving patients with permanent paraplegia, 2 underwent pump bypass and 1, the clamp/repair technique. Four other patients were seen with paraplegia or paresis and had reversal of the paralysis. The clamp/repair technique was used in these patients with clamp times ranging from 35 to 62 minutes (mean, 47.4 +/- 13.3 minutes). Renal failure did not occur in any patient, despite clamp times of up to 62 minutes (mean, 37.5 minutes). Excluding patients seen in a moribund condition, mortality most often was secondary to neurological or multisystem injury. Debate continues concerning intraoperative management of this highly lethal vascular injury. The data presented here support the historical composite experience that clamp/repair is a safe and efficacious technique that minimizes paraplegia and mortality.

Surgical management of lung bud anomalies: lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar pulmonary sequestration.

Recently we saw 9 infants with life-threatening respiratory distress. Four patients had bronchogenic cyst, 2 had cystic adenomatoid malformation, and 9 had congenital lobar emphysema. Another group of 14 older children had recurrent infection and hemodynamic abnormalities, which responded to operative intervention. Each child required an appropriate resection following definitive diagnosis. These lesions represent a spectrum of closely related anomalies that arise during an early stage of embryonic lung bud maturation. Bronchoscopy is rarely useful, but special roentgenographic studies, including perfusion scans and arteriography, are usually diagnostic. Our operative experience is used to emphasize the urgency of precise diagnosis and surgical management of this poorly recognized clinical syndrome.

Bacteremia after esophageal dilation: a clinical and experimental study.

Patients with esophageal stricture caused by caustic ingestion, reflux esophagitis, or esophageal anastomosis often require repeated dilation. These patients frequently have a short febrile course after dilation. After development of brain abscess following esophageal dilation in 1 patient, positive blood cultures were obtained in 4 patients immediately following esophageal dilation. Caustic strictures were produced in cats and esophageal dilations performed. Blood cultures were positive at one minute after dilation in 6 cats and at five minutes in 2 of those cats. The organism responsible in all clinical and three of four experimental examples was Staphylococcus aureus. It is suggested on the basis of this clinical and experimental data that patients undergoing esophageal dilation should have prophylactic coverage if they are immunosuppressed, if endocarditis prophylaxis is necessary, if they are infants, if they are diabetic, or if they had severe bacteremia following dilation.

The pathophysiology of neurofibromatosis. II. Angiosarcoma as a complication.

A patient with Von Recklinghausen neurofibromatosis and an angiosarcoma (which developed subsequent to two separate neurofibrosarcomas ) is described, and the association of neurofibromatosis and angiosarcoma is reviewed. The data showed that angiosarcoma is not coincidental with neurofibromatosis, and there is a need to focus investigative efforts on the vascular aspects of this disease.

Effect of pulmonary artery ligation on the developing fetal lung.

Ligation of the left pulmonary artery was performed in fetal lambs. The procedure was well tolerated and most animals survived to birth. At birth, the animals were in no distress but had mild pulmonary hypertension. The lung to which the pulmonary artery was ligated underwent normal intrauterine maturation.

Histochemical studies of experimental fetal intestinal obstruction.

Experimental intestinal atresia can be produced by mesenteric disruption in fetal lambs. In previous reports, a detailed histochemical study of the bowel in this atresia model demonstrated: (1) hyperplasia of ganglion cells in the dilated proximal segment, (2) involutional changes in the area of maximal distension, (3) decreased to absent adenosine triphosphatase (ATP-ase) production in the area of the atresia, (4) gradual increase of ATP-ase production to normal proximally, and (5) greater reduction of ATP-ase production along the antimesenteric border compared to the mesenteric border. In the present study, a model of fetal intestinal obstruction by simple ligation of the bowel has been created to observe the effects of pure obstruction of the lumen of the fetal bowel without the possible ischemic effects of any vascular interruption. Studies with this model reveal: (1) hyperplasia of ganglion cells in the dilated proximal segment, and (2) decreased ATP-ase production proximal to the obstruction, but (3) no involutional changes in the area of maximal distension. These findings show a pattern of disturbance of bowel morphology and function caused by obstruction of the fetal bowel that is similar to but less severe than that seen with intestinal atresia.