A micro-costing analysis of post-fracture care pathways: results from the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS).

This study identified the costs and health-related quality of life impacts of several post-fracture multidisciplinary care pathways specific to individual skeletal site (hip, distal forearm, vertebrae, humerus). These care pathways may assist healthcare providers in allocating resources for osteoporotic fractures in more effective and cost-efficient ways. INTRODUCTION: This micro-costing study was undertaken to provide the estimated healthcare costs of several fracture site-specific health service use pathways associated with different trajectories of health-related quality of life (HRQoL) 12-months post-fracture. METHODS: The study included 4126 adults aged ≥ 50 years with a fragility fracture (1657 hip, 681 vertebrae, 1354 distal forearm, 434 humerus) from the International Costs & Utilities Related to Osteoporotic fractures Study (ICUROS). ICUROS participants were asked to recall the frequency and duration (where applicable) of their health and community care service use at 4- and 12-month follow-up visits. Patient-level costs were identified and aggregated to determine the average cost of healthcare use related to the fracture in each care pathway (presented in Australian 2021 dollars). Mean cost differences were calculated and analysed using a one-way analysis of variance (ANOVA) and post hoc Bonferroni correction to determine any statistically significant differences. RESULTS: The total direct cost of fractures was estimated at $89564, $38926, $18333, and $38461AUD per patient for hip, vertebral, wrist, and humeral participants, respectively. A Kruskal-Wallis test yielded a statistically significant difference in cost values between most care pathways (p < 0.001). Of the 20 care pathways, those associated with recovery of HRQoL had lower mean costs per patient across each fracture site. CONCLUSIONS: This study identified the costs and HRQoL impacts of several multidisciplinary care pathways for individual fracture sites based on the health service utilization of an international cohort of older adults. These care pathways may assist healthcare providers in allocating resources for fragility fractures in more effective and cost-efficient ways.

Sex differences in recovery of quality of life 12 months post-fracture in community-dwelling older adults: analyses of the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS).

In this study of 695 Australian older adults (aged ≥50 years), we found that men and women had a similar trajectory of health-related quality of life (HRQoL) recovery following fragility fracture at any skeletal site. These results provide us with critical knowledge that improves our understanding of health outcomes post-fracture. INTRODUCTION: Mortality is higher in men than that in women following a fragility fracture, but it is unclear whether recovery of patient-reported outcomes such as health-related quality of life (HRQoL) differs between sexes. This study aimed to identify sex differences in HRQoL recovery 12 months post-fracture. METHODS: Data were from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS). Participants recruited to AusICUROS were adults aged ≥50 years who sustained a fragility fracture. HRQoL was measured using the EQ-5D-3L at three time-points post-fracture: within 2 weeks (including pre-fracture recall) and at 4 and 12 months. Multivariate logistic regression analyses were undertaken, adjusting for confounders including age, education, income, and healthcare utilization post-fracture. RESULTS: Overall, 695 AusICUROS participants (536 women, 77.1%) were eligible for analysis with fractures at the hip (n = 150), distal forearm (n = 261), vertebrae (n = 61), humerus (n = 52), and other skeletal sites (n = 171). At the time of fracture, men were younger, reported a higher income, and were more likely to be employed, compared with women. For all fracture sites combined, there were no differences between men and women in recovery to pre-fracture HRQoL at 12-month follow-up (adjusted OR = 1.09; 95% CI: 0.75-1.61). When stratified by fracture site, no significant sex differences were seen for hip (OR = 1.02; 95% CI: 0.42-2.52), distal forearm (OR = 1.60; 95% CI: 0.68-3.78), vertebral (OR = 2.28; 95% CI: 0.61-8.48), humeral (OR = 1.62; 95% CI: 0.16-9.99), and other fractures (OR = 1.00; 95% CI: 0.44-2.26). CONCLUSION: Community-dwelling men and women who survived the 12 months following fragility fracture had a similar trajectory of HRQoL recovery at any skeletal site.

Development and validation of the risk engine for an Australian Health Economics Model of Osteoporosis.

The Australian Health Economics Model of Osteoporosis (AusHEMO) has shown good face, internal and cross validities, and can be used to assist healthcare decision-making in Australia. PURPOSE: This study aimed to document and validate the risk engine of the Australian Health Economics Model of Osteoporosis (AusHEMO). METHODS: AusHEMO is a state-transition microsimulation model. The fracture risks were simulated using fracture incidence rates from the Dubbo Osteoporosis Epidemiology Study. The AusHEMO was validated regarding its face, internal and cross validities. Goodness-of-fit analysis was conducted and Lin's coefficient of agreement and mean absolute difference with 95% limits of agreement were reported. RESULTS: The development of AusHEMO followed general and osteoporosis-specific health economics guidelines. AusHEMO showed good face validity regarding the model's structure, evidence, problem formulation and results. In addition, the model has been proven good internal and cross validities in goodness-of-fit test. Lin's coefficient was 0.99, 1 and 0.94 for validation against the fracture incidence rates, Australian life expectancies and residual lifetime fracture risks, respectively. CONCLUSIONS: In summary, the development of the risk engine of AusHEMO followed the best practice for osteoporosis disease modelling and the model has been shown to have good face, internal and cross validities. The AusHEMO can be confidently used to predict long-term fracture-related outcomes and health economic evaluations when costs data are included. Health policy-makers in Australia can use the AusHEMO to select which osteoporosis interventions such as medications and public health interventions represent good value for money.

Prediction models and questionnaires developed to predict vitamin D status in adults: a systematic review.

A systematic review of prediction models/questionnaires developed to identify people with deficient/insufficient vitamin D status shows the potential of self-reported information to estimate vitamin D status. The objective is to identify and compare existing screening tools, developed to identify vitamin D deficiency or insufficiency in adults. A systematic search of literature was conducted using MEDLINE, Scopus, Web of Science and CINAHL databases. Risk of bias and applicability concerns were assessed by quality assessment of diagnostic accuracy studies (QUADAS-2). Data were extracted on socio-demographic, anthropometric, risk factors, serum 25 hydroxyvitamin D [25(OH)D] levels, statistical methods and predictive ability. A total of 12 studies were considered for inclusion for this systematic review after screening of 4851 abstracts and 15 full-text articles. Ten of twelve studies developed prediction models and 2 studies developed questionnaires. The majority of studies had low risk of bias and applicability as assessed by QUADAS-2. All studies included only self-reported predictors of vitamin D status in their final models and development of scores. Sunlight exposure and related factors were important significant contributors to the predictive ability of the models and/or questionnaires. Sensitivity and specificity of the prediction models or questionnaires ranged from 55 to 91% and 35 to 84%, respectively. Six out of twelve studies converted final models to scores associated with vitamin D status. There was no evidence that any of these existing tools have been translated into clinical practice. The prediction models or questionnaires identified in this systematic review were moderately sensitive and specific for identifying people with vitamin D deficiency or insufficiency. The substantial contribution of sunlight exposure to the prediction of vitamin D status highlights the importance of including this information when developing vitamin D screening tools.

Impact of acute stress on itch sensation and scratching behaviour in patients with atopic dermatitis and healthy controls.

BACKGROUND: Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and scratching behaviour in these patients. OBJECTIVES: We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD. METHODS: The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off-site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes). RESULTS: In patients with AD, stress induced by TSST caused a significant reduction of cowhage-evoked itch but significantly increased off-site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema. CONCLUSIONS: We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress-related exacerbation of itch in patients with AD.

Characteristics of recurrent fractures.

The present study, drawn from a sample of the Icelandic population, quantified high immediate risk and utility loss of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) that attenuated with time. INTRODUCTION: The risk of a subsequent osteoporotic fracture is particularly acute immediately after an index fracture and wanes progressively with time. The aim of this study was to quantify the risk and utility consequences of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) with an emphasis on the time course of recurrent fracture. METHODS: The Reykjavik Study fracture registration, drawn from a sample of the Icelandic population (n = 18,872), recorded all fractures of the participants from their entry into the study until December 31, 2012. Medical records for the participants were manually examined and verified. First sentinel fractures were identified. Subsequent fractures, deaths, 10-year probability of fracture and cumulative disutility using multipliers derived from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) were examined as a function of time after fracture, age and sex. RESULTS: Over 10 years, subsequent fractures were sustained in 28% of 1498 individuals with a sentinel hip fracture. For other sentinel fractures, the proportion ranged from 35 to 38%. After each sentinel fracture, the risk of subsequent fracture was highest in the immediate post fracture interval and decreased markedly with time. Thus, amongst individuals who sustained a recurrent fracture, 31-45% did so within 1 year of the sentinel fracture. Hazard ratios for fracture recurrence (population relative risks) were accordingly highest immediately after the sentinel fracture (2.6-5.3, depending on the site of fracture) and fell progressively over 10 years (1.5-2.2). Population relative risks also decreased progressively with age. The utility loss during the first 10 years after a sentinel fracture varied by age (less with age) and sex (greater in women). In women at the age of 70 years, the mean utility loss due to fractures in the whole cohort was 0.081 whereas this was 12-fold greater in women with a sentinel hip fracture, and was increased 15-fold for spine fracture, 4-fold for forearm fracture and 8-fold for humeral fracture. CONCLUSION: High fracture risks and utility loss immediately after fracture suggest that treatment given as soon as possible after fracture would avoid a higher number of new fractures compared with treatment given later. This provides the rationale for very early intervention immediately after a sentinel fracture.

Quality of life for up to 18 months after low-energy hip, vertebral, and distal forearm fractures-results from the ICUROS.

This study used data from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) to estimate the quality of life (QoL) impact of fracture. Hip, vertebral, and distal forearm fractures incur substantial QoL losses. Hip and vertebral fracture results in markedly impaired QoL for at least 18 months. INTRODUCTION: The International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) is a multinational observational study that aims to describe costs and quality of life (QoL) consequences of osteoporotic fractures. To date, 11 countries have participated in the study: Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain, the UK, and the USA. The objective of this paper is to describe the QoL impact of hip, vertebral, and distal forearm fracture. METHODS: Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall) and at 4, 12, and 18 months after fracture. Quality of life was measured as health state utility values (HSUVs) derived from the EQ-5D-3L. Complete case analysis was conducted as the base case with available case and multiple imputation performed as sensitivity analyses. Multivariate analysis was performed to explore predictors of QoL impact of fracture. RESULTS: Among 5456 patients enrolled using convenience sampling, 3021 patients were eligible for the base case analysis (1415 hip, 1047 distal forearm, and 559 vertebral fractures). The mean (SD) difference between HSUV before and after fracture for hip, vertebral, and distal forearm fracture was estimated at 0.89 (0.40), 0.67 (0.45), and 0.48 (0.34), respectively (p < 0.001 for all fracture types). Eighteen months after fracture, mean HSUVs were lower than before the fracture in patients with hip fracture (0.66 vs. 0.77 p < 0.001) and vertebral fracture (0.70 vs. 0.83 p < 0.001). Hospitalization and higher recalled pre-fracture QoL were associated with increased QoL impact for all fracture types. CONCLUSIONS: Hip, vertebral, and distal forearm fractures incur substantial loss in QoL and for patients with hip or vertebral fracture, QoL is markedly impaired for at least 18 months.

ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter.

KEY POINTS: The internal anal sphincter develops tone important for maintaining high anal pressure and continence. Controversy exists regarding the mechanisms underlying tone development. We examined the hypothesis that tone depends upon electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC-IM) by activation of Ca2+ -activated Cl- channels (ANO1, encoded by Ano1) and voltage-dependent L-type Ca2+ channels (CavL , encoded by Cacna1c). Measurement of membrane potential and contraction indicated that ANO1 and CavL have a central role in SW generation, phasic contractions and tone, independent of stretch. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Ano1 and Cacna1c expression levels were examined by quantitative PCR in fluorescence-activated cell sorting. ICC-IM were the predominant cell type expressing ANO1 and the most likely candidate for SW generation. SWs in ICC-IM are proposed to conduct to smooth muscle where Ca2+ entry via CavL results in phasic activity that sums to produce tone. ABSTRACT: The mechanism underlying tone generation in the internal anal sphincter (IAS) is controversial. We examined the hypothesis that tone depends upon generation of electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC-IM) by activation of Ca2+ -activated Cl- channels (encoded by Ano1) and voltage-dependent L-type Ca2+ channels (encoded by Cacna1c). Phasic contractions and tone in the IAS were nearly abolished by ANO1 and CavL antagonists. ANO1 antagonists also abolished SWs as well as transient depolarizations that persisted after addition of CavL antagonists. Tone development in the IAS did not require stretch of muscles, and the sensitivity of contraction to ANO1 antagonists was the same in stretched versus un-stretched muscles. ANO1 expression was examined in wildtype and Ano1/+egfp mice with immunohistochemical techniques. Dual labelling revealed that ANO1 expression could be resolved in ICC but not smooth muscle cells (SMCs) in the IAS and rectum. Ano1, Cacna1c and Kit gene expression were the same in extracts of IAS and rectum muscles. In IAS cells isolated with fluorescence-activated cell sorting, Ano1 expression was 26.5-fold greater in ICC than in SMCs while Cacna1c expression was only 2-fold greater in SMCs than in ICC. These data support a central role for ANO1 and CavL in the generation of SWs and tone in the IAS. ICC-IM are the probable cellular candidate for ANO1 currents and SW generation. We propose that ANO1 and CavL collaborate to generate SWs in ICC-IM followed by conduction to adjacent SMCs where phasic calcium entry through CavL sums to produce tone.

Diversity in fall characteristics hampers effective prevention: the precipitants, the environment, the fall and the injury.

Falls among the elderly are common and characteristics may differ between injurious and non-injurious falls. Among 887 older Australian women followed for 1.6 years, 32% fell annually. Only 8.5% resulted in fracture and/or hospital admission. The characteristics of those falls are indistinguishable from those not coming to medical attention. INTRODUCTION: The precipitants and environment of all falls occurring among a large cohort of older Caucasian women were categorised by injury status to determine if the characteristics differed between injurious and non-injurious falls. METHODS: Among 887 Australian women (70+ years), falls were ascertained using monthly postcard calendars and a questionnaire was administered for each fall. Hospital admissions and fractures were independently confirmed. RESULTS: All falls were reported for a mean observation time of 577 (IQR 546-607) days per participant, equating to a total 1400 person-years. Thirty-two percent fell at least once per year. The most common features of a fall were that the faller was walking (61%) at home (61%) during the day (88%) and lost balance (32%). Only 12% of all falls occurred at night. Despite no difference in the type of injury between day and night, the likelihood of being hospitalised from a fall at night was 4.5 times greater than that of a daytime fall with adjustment for injury type and participant age (OR 4.5, 95% CI 2.1, 9.5; p < 0.001). Of all falls, approximately one third were associated with no injury to the faller (31%), one third reported a single injury (37%) and one third reported more than one injury (32%). In 95% of falls, the faller was not admitted to hospital. Only 5% of falls resulted in fracture(s). CONCLUSIONS: Our findings demonstrate the significant diversity of precipitants and environment where falls commonly occur among older community-dwelling women. Falls resulting in fracture and/or hospital admission collectively represent 8.5% of all falls and their characteristics are indistinguishable from falls not coming to medical attention and incurring no apparent cost to the health system.

Non-hip and non-vertebral fractures: the neglected fracture sites.

SUMMARY: Non-hip, non-vertebral fractures (NHNVF) were compared with hip, vertebral and controls. NHNVF were younger and heavier than controls and hip/vertebral fractures in both men and women, respectively. Falls and prior fractures were less common in NHNVF than hip fractures. Glucocorticoid use was lower in NHNVF compared to vertebral fracture (VF) in men. INTRODUCTION: Although hip fracture (HF) and vertebral fractures (VF) receive the most attention in the literature and are the targeted sites for fracture prevention, non-hip, non-vertebral fracture (NHNVF) sites account for a greater proportion of fractures than the hip or vertebrae. This study aimed to assess risk factors for NHNVF and compare them with those for HF, VF and controls. METHODS: Incident fractures during 2005-2007 for men and 1994-1996 for women were identified using computerised keyword searches of radiological reports, and controls were selected at random from electoral rolls for participation in the Geelong Osteoporosis Study. Participants aged 60+ years were included in this study. RESULTS: Compared to controls, men and women with NHNVF were younger (ORs, 0.90, 95% CI 0.86-0.94; and 0.96, 0.93-0.98, respectively) and had a lower femoral neck bone mineral density (BMD) T-score (age-adjusted; difference [men] 0.383, P = 0.002; [women] 0.287, P = 0.001). Compared to HF, men and women with NHNVF were heavier (difference [men] 9.0 kg, P = 0.01; [women] 7.6 kg, P < 0.001). Heavier weight was also a risk factor for women with NHNVF compared to VF (1.03, 1.01-1.06). In men with NHNVF, falls (0.37, 0.14-0.97) and prior fractures (0.38, 0.15-0.98) were less common compared to HF; and glucocorticoid use was less common for NHNVF (0.30, 0.11-0.85) compared to VF. CONCLUSIONS: Given the high numbers of NHNVF sustained by men and women in this study, fracture prevention strategies should focus on individuals with high risk of sustaining these types of fractures, as well as on individuals who are more likely to sustain a HF or VF.

Changes in quality of life associated with fragility fractures: Australian arm of the International Cost and Utility Related to Osteoporotic Fractures Study (AusICUROS).

UNLABELLED: We investigated change in health-related quality of life due to fracture in Australian adults aged over 50 years. Fractures reduce quality of life with the loss sustained at least over 12 months. At a population level, the loss was equivalent to 65 days in full health per fracture. PURPOSE: We aimed to quantify the change in health-related quality of life (HRQoL) that occurred as a consequence of a fracture using the EQ-5D-3 L questionnaire. METHODS: Adults aged ≥50 years with a low to moderate energy fracture were recruited from eight study centres across Australia. This prospective study included an 18-month follow-up of participants recruited within 2 weeks of a fracture (hip, wrist, humerus, vertebral and ankle). Information collected at baseline and 4, 12 and 18 months included characteristics of participants such as income level, education and prior fracture status. At 12 months post-fracture, the cumulative loss of quality of life was estimated using multivariate regression analysis to identify the predictors of HRQoL loss. RESULTS: Mean HRQoL for all participants before fracture was 0.86, with wrist fracture having the highest pre-fracture HRQoL (0.90), while vertebral fracture had the lowest (0.80). HRQoL declined to 0.42 in the immediate post-fracture period. Only participants with a wrist, humerus or ankle fracture returned to their pre-fracture HRQoL after 18 months. An increased loss of HRQoL over 12 months was associated with HRQoL prior to the fracture, hospitalisation, education and fracture site. The multiple regression explained 30 % of the variation in the cumulative HRQoL loss at 12 months post-fracture for all fractures. CONCLUSION: Low to moderate energy fractures reduce HRQoL, and this loss is sustained for at least 12 months or, in the case of hip and spine fractures, at least 18 months. At a population level, this represents an average loss of 65 days in full health per fragility fracture. This significant burden reinforces the need for cost-effective fracture prevention strategies.

Associations of calf inter- and intra-muscular adipose tissue with cardiometabolic health and physical function in community-dwelling older adults.

OBJECTIVES: To determine associations of inter- and intra-muscular adipose tissue (IMAT) with cardiometabolic health and physical function in older adults. METHODS: 48 community-dwelling older adults aged ⋝65 years (mean 71.6±4.8 years; 52% women) underwent whole-body dual-energy X-ray absorptiometry, to assess appendicular lean mass (ALM), and peripheral quantitative computed tomography (pQCT; 66% tibia), to assess calf IMAT cross-sectional area ([CSA]; cm2) and muscle density (mg/cm(3); higher values indicate lower fat infiltration). Fasting glucose, lipids, triglycerides and C-reactive protein (CRP) were analysed. Physical function was assessed by postural sway (computerised posturography; N=41), and gait analysis (GAITRite Electronic Walkway; N=40). RESULTS: Higher IMAT CSA and muscle density were associated with significantly higher (B=0.85 95%CI [0.34, 1.36]) and lower (-2.14 [-4.20, -0.08]) CRP and higher (0.93 [0.56, 1.30]) and lower postural sway (-3.12 [-4.74, -1.50]), respectively, after adjustment for age, sex and ALM/BMI. Higher IMAT CSA was associated with slower gait speed and cadence, and greater step time and step width (all P<0.03), while higher muscle density was associated with smaller step width (P<0.01) only. CONCLUSIONS: Older adults with higher calf IMAT have poorer balance, mobility and inflammatory status. Interventions aimed at improving physical function in older adults should incorporate strategies to reduce IMAT.

Nitrergic neuromuscular transmission in the mouse internal anal sphincter is accomplished by multiple pathways and postjunctional effector cells.

The effector cells and second messengers participating in nitrergic neuromuscular transmission (NMT) were investigated in the mouse internal anal sphincter (IAS). Protein expression of guanylate cyclase (GCα, GCß) and cyclic GMP-dependent protein kinase I (cGKI) were examined in cryostat sections with dual-labeling immunohistochemical techniques in PDGFRα(+) cells, interstitial cells of Cajal (ICC), and smooth muscle cells (SMC). Gene expression levels were determined with quantitative PCR of dispersed cells from Pdgfrα(egfp/+), Kit(copGFP/+), and smMHC(Cre-egfp) mice sorted with FACS. The relative gene and protein expression levels of GCα and GCß were PDGFRα(+) cells > ICC ≫ SMC. In contrast, cGKI gene expression sequence was SMC = ICC > PDGFRα(+) cells whereas cGKI protein expression sequence was neurons > SMC ≫ ICC = PDGFRα(+) cells. The functional role of cGKI was investigated in cGKI(-/-) mice. Relaxation with 8-bromo (8-Br)-cGMP was greatly reduced in cGKI(-/-) mice whereas responses to sodium nitroprusside (SNP) were partially reduced and forskolin responses were unchanged. A nitrergic relaxation occurred with nerve stimulation (NS, 5 Hz, 60 s) in cGKI(+/+) and cGKI(-/-) mice although there was a small reduction in the cGKI(-/-) mouse. N(ω)-nitro-l-arginine (l-NNA) abolished responses during the first 20-30 s of NS in both animals. The GC inhibitor ODQ greatly reduced or abolished SNP and nitrergic NS responses in both animals. These data confirm an essential role for GC in NO-induced relaxation in the IAS. However, the expression of GC and cGKI by all three cell types suggests that each may participate in coordinating muscular responses to NO. The persistence of nitrergic NMT in the cGKI(-/-) mouse suggests the presence of a significant GC-dependent, cGKI-independent pathway.

Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults.

UNLABELLED: Sarcopenia may be diagnosed in the clinic using operational definitions based on low muscle mass or function. This prospective, population-based study revealed that sex-specific associations may exist between operational definitions of sarcopenia and falls in community-dwelling middle-aged and older adults. INTRODUCTION: The objective of this study is to verify associations between sarcopenia and falls risk and to determine changes in sarcopenia prevalence over 5 years in middle-aged and older men and women according to different anthropometric and performance-based operational definitions. METHODS: N = 681 volunteers (48% female; mean ± SD age 61.4 ± 7.0 years) participated in baseline and follow-up assessments (mean 5.1 ± 0.5 years later). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry, hand grip (HGS) and lower-limb (LLS) strength were assessed by dynamometry, and falls risk was determined using the physiological profile assessment. Anthropometric definitions (ALM/height squared [ALM-H], ALM/weight × 100 and a residuals method [ALM-R]) and performance-based definitions (HGS, LLS and upper- and lower-limb muscle quality [LMQ]) of sarcopenia were examined. The lowest 20% of the sex-specific distribution for each definition at baseline was classified as sarcopenia. RESULTS: Sarcopenia prevalence increased after 5 years for all operational definitions except ALM-H (men: -4.0%; women: -5.5%). Men classified with sarcopenia according to anthropometric definitions, and women classified with sarcopenia according to performance-based definitions, had significant increases in falls risk over 5 years (all P < 0.05) compared to individuals without sarcopenia. Significant sex interactions were observed for ALM-R, LLS and LMQ (all P < 0.05) definitions. CONCLUSIONS: Sarcopenia prevalence generally increases at a higher rate when assessed using performance-based definitions. Sarcopenia is associated with increases in falls risk over 5 years in community-dwelling middle-aged and older adults, but sex-specific differences may exist according to different anthropometric or performance-based definitions.

The International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS)--quality of life during the first 4 months after fracture.

UNLABELLED: The quality of life during the first 4 months after fracture was estimated in 2,808 fractured patients from 11 countries. Analysis showed that there were significant differences in the quality of life (QoL) loss between countries. Other factors such as QoL prior fracture and hospitalisation also had a significant impact on the QoL loss. INTRODUCTION: The International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS) was initiated in 2007 with the objective of estimating costs and quality of life related to fractures in several countries worldwide. The ICUROS is ongoing and enrols patients in 11 countries (Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain, UK and the USA). The objective of this paper is to outline the study design of ICUROS and present results regarding the QoL (measured using the EQ-5D) during the first 4 months after fracture based on the patients that have been thus far enrolled ICUROS. METHODS: ICUROS uses a prospective study design where data (costs and quality of life) are collected in four phases over 18 months after fracture. All countries use the same core case report forms. Quality of life was collected using the EQ-5D instrument and a time trade-off questionnaire. RESULTS: The total sample for the analysis was 2,808 patients (1,273 hip, 987 distal forearm and 548 vertebral fracture). For all fracture types and countries, the QoL was reduced significantly after fracture compared to pre-fracture QoL. A regression analysis showed that there were significant differences in the QoL loss between countries. Also, a higher level of QoL prior to the fracture significantly increased the QoL loss and patients who were hospitalised for their fracture also had a significantly higher loss compared to those who were not. CONCLUSIONS: The findings in this study indicate that there appear to be important variations in the QoL decrements related to fracture between countries.

Detection of TiO2 nanoparticles in cells by flow cytometry.

Evaluation of the potential hazard of man-made nanomaterials has been hampered by a limited ability to observe and measure nanoparticles in cells. In this study, different concentrations of TiO(2) nanoparticles were suspended in cell culture medium. The suspension was then sonicated and characterized by dynamic light scattering and microscopy. Cultured human-derived retinal pigment epithelial cells (ARPE-19) were incubated with TiO(2) nanoparticles at 0, 0.1, 0.3, 1, 3, 10, and 30 microg/ml for 24 hours. Cellular reactions to nanoparticles were evaluated using flow cytometry and dark field microscopy. A FACSCalibur flow cytometer was used to measure changes in light scatter after nanoparticle incubation. Both the side scatter and forward scatter changed substantially in response to the TiO(2). From 0.1 to 30 microg/ml TiO(2), the side scatter increased sequentially while the forward scatter decreased, presumably due to substantial light reflection by the TiO(2) particles. Based on the parameters of morphology and the calcein-AM/propidium iodide viability assay, TiO(2) concentrations below 30 microg/ml TiO(2) caused minimal cytotoxicity. Microscopic analysis was done on the same cells using an E-800 Nikon microscope containing a xenon light source and special dark field objectives. At the lowest concentrations of TiO(2) (0.1-0.3 microg/ml), the flow cytometer could detect as few as 5-10 nanoparticles per cell due to intense light scattering by TiO(2). Rings of concentrated nanoparticles were observed around the nuclei in the vicinity of the endoplasmic reticulum at higher concentrations. These data suggest that the uptake of nanoparticles within cells can be monitored with flow cytometry and confirmed by dark field microscopy. This approach may help fulfill a critical need for the scientific community to assess the relationship between nanoparticle dose and cellular toxicity Such experiments could potentially be performed more quickly and easily using the flow cytometer to measure both nanoparticle uptake and cellular health.

Biophysically based mathematical modeling of interstitial cells of Cajal slow wave activity generated from a discrete unitary potential basis.

Spontaneously rhythmic pacemaker activity produced by interstitial cells of Cajal (ICC) is the result of the entrainment of unitary potential depolarizations generated at intracellular sites termed pacemaker units. In this study, we present a mathematical modeling framework that quantitatively represents the transmembrane ion flows and intracellular Ca2+ dynamics from a single ICC operating over the physiological membrane potential range. The mathematical model presented here extends our recently developed biophysically based pacemaker unit modeling framework by including mechanisms necessary for coordinating unitary potential events, such as a T-Type Ca2+ current, Vm-dependent K+ currents, and global Ca2+ diffusion. Model simulations produce spontaneously rhythmic slow wave depolarizations with an amplitude of 65 mV at a frequency of 17.4 cpm. Our model predicts that activity at the spatial scale of the pacemaker unit is fundamental for ICC slow wave generation, and Ca2+ influx from activation of the T-Type Ca2+ current is required for unitary potential entrainment. These results suggest that intracellular Ca2+ levels, particularly in the region local to the mitochondria and endoplasmic reticulum, significantly influence pacing frequency and synchronization of pacemaker unit discharge. Moreover, numerical investigations show that our ICC model is capable of qualitatively replicating a wide range of experimental observations.

Establishing an Operational Definition of Sarcopenia in Australia and New Zealand: Delphi Method Based Consensus Statement.

BACKGROUND: Globally there are several operational definitions for sarcopenia, complicating clinical and research applications. OBJECTIVE: The objective of the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Task Force on Diagnostic Criteria for Sarcopenia was to reach consensus on the operational definition of sarcopenia for regional use by clinicians and researchers. METHOD: A four-Phase modified Delphi process was undertaken in which 24 individuals with expertise or a recognised interest in sarcopenia from different fields across Australia and New Zealand were invited to be Task Force members. An initial face-to-face meeting was held in Adelaide, South Australia, in November 2017, followed by two subsequent online Phases conducted by electronic surveys. A final Phase was used to approve the final statements. Responses were analysed using a pre-specified strategy. The level of agreement required for consensus was 80%. RESULTS: In Phase 2, 94.1% of Task Force respondents voted in favour of adopting an existing operational definition of sarcopenia. In Phase 3, 94.4% of respondents voted in favour of adopting the European Working Group on Sarcopenia in Older People (EWGSOP) definition as the operational definition for sarcopenia in Australia and New Zealand. CONCLUSION: With consensus achieved, the ANZSSFR will adopt, promote and validate the EWGSOP operational definition of sarcopenia for use by clinicians and researchers in Australia and New Zealand.

A biophysically based mathematical model of unitary potential activity in interstitial cells of Cajal.

Unitary potential (UP) depolarizations are the basic intracellular events responsible for pacemaker activity in interstitial cells of Cajal (ICCs), and are generated at intracellular sites termed "pacemaker units". In this study, we present a mathematical model of the transmembrane ion flows and intracellular Ca(2+) dynamics from a single ICC pacemaker unit acting at near-resting membrane potential. This model quantitatively formalizes the framework of a novel ICC pacemaking mechanism that has recently been proposed. Model simulations produce spontaneously rhythmic UP depolarizations with an amplitude of approximately 3 mV at a frequency of 0.05 Hz. The model predicts that the main inward currents, carried by a Ca(2+)-inhibited nonselective cation conductance, are activated by depletion of sub-plasma-membrane [Ca(2+)] caused by sarcoendoplasmic reticulum calcium ATPase Ca(2+) sequestration. Furthermore, pacemaker activity predicted by our model persists under simulated voltage clamp and is independent of [IP(3)] oscillations. The model presented here provides a basis to quantitatively analyze UP depolarizations and the biophysical mechanisms underlying their production.