Incremental costs of fragility fractures: a population-based matched -cohort study from Ontario, Canada.

Using a matched cohort design, the 1-year excess cost of incident fragility fractures at any site was $26,341 per patient, with 43% of total excess costs attributed to hospitalization. The high economic burden of fractures in Ontario underscores the urgency of closing the secondary fracture prevention gap. INTRODUCTION: This retrospective real-world observational study was conducted to document the incremental costs associated with fragility fractures in Ontario, Canada. METHODS: Patients aged >65 years with an index fragility fracture occurring between January 2011 and March 2015 were identified from administrative databases and matched 1:1 to a cohort of similar patients without a fracture. Healthcare resource utilization data were extracted from healthcare records and associated costs were calculated on a per-patient level and for the province of Ontario. Costs were presented as 2017 Canadian dollars. RESULTS: The eligible cohort included 115,776 patients with a fragility fracture. Of these, 101,773 patients were successfully matched 1:1 to a non-fracture cohort. Overall, hip fractures (n = 31,613) were the most common, whereas femur fractures (n = 3002) were the least common type. Hospitalization and continuing care/home care/long-term care accounted for more than 60% of 1-year direct costs, whereas 5% was attributed to medication costs. First-year costs per patient in the fracture cohort were approximately threefold higher versus the non-fracture cohort (mean $37,362 versus $11,020, respectively). The incremental first-year direct healthcare costs of fragility fractures for the province of Ontario were calculated at $724 million per year. CONCLUSIONS: Fragility fractures were associated with a threefold increase in overall mean healthcare costs per patient compared to patients without fractures. With an aging population, there is an urgent need for improved prevention strategies for patients at high-risk of fracture to decrease the economic burden of fragility fractures on the Canadian healthcare system.

A scorecard for osteoporosis in Canada and seven Canadian provinces.

The scorecard evaluates the burden and management of osteoporosis in Canada and how care pathways differ across Canadian provinces. The results showed there are inequities in patients' access to diagnosis, treatment, and post-fracture care programs in Canada. Interventions are needed to close the osteoporosis treatment gap and minimize these inequities. INTRODUCTION: The purpose of this study was to develop a visual scorecard that assesses the burden of osteoporosis and its management within Canada and seven Canadian provinces. METHODS: We adapted the Scorecard for Osteoporosis in Europe (SCOPE) to score osteoporosis indicators for Canada and seven provinces (British Columbia, Alberta, Saskatchewan, Ontario, Quebec, New Brunswick, and Newfoundland). We obtained data from a comprehensive literature review and interviews with osteoporosis experts. We scored 20 elements across four domains: burden of disease, policy framework, service provision, and service uptake. Each element was scored as red, yellow, or green, indicating high, intermediate, or low risk, respectively. Elements with insufficient data were scored black. RESULTS: Canada performed well on several elements of osteoporosis care, including high uptake of risk assessment algorithms and minimal wait times for hip fracture surgery. However, there were no established fracture registries, and reporting on individuals with high fracture risk who remain untreated was limited. Furthermore, osteoporosis was not an official health priority in most provinces. Government-backed action plans and other osteoporosis initiatives were primarily confined to Ontario and Alberta. Several provinces (Saskatchewan, New Brunswick, Newfoundland) did not have any registered fracture liaison service (FLS) programs. Access to diagnosis and treatment was also inconsistent and reimbursement policies did not align with clinical guidelines. CONCLUSION: Government-backed action plans are needed to address provincial inequities in patients' access to diagnosis, treatment, and FLS programs in Canada. Further characterization of the treatment gap and the establishment of fracture registries are critical next steps in providing high-quality osteoporosis care.

Synthetic Polyampholytes as Macromolecular Cryoprotective Agents.

A series of polyampholytes based on different molar ratios on N, N-dimethylaminopropyl methacrylamide (DMAPMA), acrylic acid (AA), and optionally, N- tert-butylacrylamide ( t-BuAAm), were prepared by free radical copolymerization, and tested as DMSO-free cryoprotective agents for 3T3 fibroblast cells by using a standard freeze-rethaw protocol. Polybetaines prepared by reaction of DMAPMA homo and copolymers with 1,3-propane sultone were used as additional controls. Results showed strong effects of copolymer composition, molecular weight, polymer and NaCl concentrations, on post-thaw cell viability. Binary (DMAPMA/AA) copolymers showed best post-thaw cell viability of 70% at a 30/70 mol % ratio of DMAPMA/AA, which increased to 90% upon introduction of 9 mol % t-BuAAm while maintaining the 30/70 mol % cation/anion ratio. The use of acrylamide linkages in DMAPMA ensures absence of hydrolytic loss of cationic side chains. These polyampholytes were found to decrease ice crystal size and to form a polymer-rich, ice-free layer around cells, reducing damage from intercellular ice crystals during both freezing and thawing steps. These polyampholytes also dehydrate cells during freezing, which helps protect cells from intracellular ice damage. While cell viability immediately after thawing was high, subsequent culturing revealed poor attachment and long-term viability, which is attributed to residual cell damage from intracellular ice formation. Addition of 2 wt % DMSO or 1% BSA to the polymer-based freeze medium was found to mitigate this damage and result in post-thaw viabilities matching those achieved with 10 wt % DMSO.

Sonographic markers of fetal adiposity and risk of Cesarean delivery.

OBJECTIVE: Increased fetal size is associated with shoulder dystocia during labor and subsequent need for assisted delivery. We sought to investigate if increased fetal adiposity diagnosed sonographically in late pregnancy is associated with increased risk of operative delivery. METHODS: This secondary analysis of the Genesis Study recruited 2392 nulliparous women with singleton pregnancy in cephalic presentation, in a prospective, multicenter study, to examine prenatal and intrapartum predictors of Cesarean delivery. Participants underwent ultrasound and clinical evaluation between 39 + 0 and 40 + 6 weeks' gestation. Data on fetal biometry were not revealed to patients or to their managing clinicians. A fetal adiposity composite of fetal thigh adiposity and fetal abdominal wall thickness was compiled for each infant in order to determine whether fetal adiposity > 90th centile was associated with an increased risk of Cesarean or operative vaginal delivery. RESULTS: After exclusions, data were available for 2330 patients. Patients with a fetal adiposity composite > 90th centile had a higher maternal body mass index (BMI) (25 ± 5 kg/m2 vs 24 ± 4 kg/m2 ; P = 0.005), birth weight (3872 ± 417 g vs 3585 ± 401 g; P < 0.0001) and rate of induction of labor (47% (108/232) vs 40% (834/2098); P = 0.048) than did those with an adiposity composite ≤ 90th centile. Fetuses with adiposity composite > 90th centile were more likely to require Cesarean delivery than were those with adiposity composite ≤ 90th centile (P < 0.0001). After adjusting for birth weight, maternal BMI and need for induction of labor, fetal adiposity > 90th centile remained a risk factor for Cesarean delivery (P < 0.0001). A fetal adiposity composite > 90th centile was more predictive of the need for unplanned Cesarean delivery than was an estimated fetal weight > 90th centile (odds ratio, 2.20 (95% CI, 1.65-2.94; P < 0.001) vs 1.74 (95% CI, 1.29-2.35; P < 0.001). Having an adiposity composite > 90th centile was not associated with an increased likelihood of operative vaginal delivery when compared with having an adiposity composite ≤ 90th centile (P = 0.37). CONCLUSIONS: Fetuses with increased adipose deposition are more likely to require Cesarean delivery than are those without increased adiposity. Consideration should, therefore, be given to adding fetal thigh adiposity and abdominal wall thickness to fetal sonographic assessment in late pregnancy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Synthetic hydrogels formed by thiol-ene crosslinking of vinyl sulfone-functional poly(methyl vinyl ether-alt-maleic acid) with α,ω-dithio-polyethyleneglycol.

Polymer hydrogels formed by rapid thiol-ene coupling of macromolecular gel formers can offer access to versatile new matrices. This paper describes the efficient synthesis of cysteamine vinyl sulfone (CVS) trifluoroacetate, and its incorporation into poly(methyl vinyl ether-alt-maleic anhydride) (PMMAn) to form a series of CVS-functionalized poly(methyl vinyl ether-alt-maleic acid) polymers (PMM-CVSx) containing 10 to 30 mol% pendant vinyl sulfone groups. Aqueous mixtures of these PMM-CVS and a dithiol crosslinker, α,ω-dithio-polyethyleneglycol (HS-PEG-SH, Mn = 1 kDa), gelled through crosslinking by Michael addition within seconds to minutes, depending on pH, degree of functionalization, and polymer loading. Gelation efficiency, Young's modulus, equilibrium swelling and hydrolytic stability are described, and step-wise hydrogel post-functionalization with a small molecule thiol, cysteamine, was demonstrated. Cytocompatibility of these crosslinked hydrogels towards entrapped 3T3 fibroblasts was confirmed using a live/dead fluorescence assay.

Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning.

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 µM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 µM vs C eff = 0.04 ± 0.04 µM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.

Establishment of a cell line for assessing drugs as canine P-glycoprotein substrates: proof of principle.

P-glycoprotein (P-gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P-gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P-gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P-gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P-gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P-gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1-1Δ) or acquired (drug interactions between a P-gp inhibitor and P-gp substrate). New human drug candidates are required to undergo assessment for P-gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug-drug interactions. Similar information regarding canine P-gp could prevent adverse drug reactions in dogs. Because differences in P-gp substrates have been documented between species, one should not presume that human or murine P-gp substrates are necessarily canine P-gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P-gp substrates.

The current economic burden of illness of osteoporosis in Canada.

UNLABELLED: We estimate the current burden of illness of osteoporosis in Canada is double ($4.6 billion) our previous estimates ($2.3 billion) due to improved data capture of the multiple encounters and services that accompany a fracture: emergency room, admissions to acute and step-down non-acute institutions, rehabilitation, home-assisted or long-term residency support. INTRODUCTION: We previously estimated the economic burden of illness of osteoporosis-attributable fractures in Canada for the year 2008 to be $2.3 billion in the base case and as much as $3.9 billion. The aim of this study is to update the estimate of the economic burden of illness for osteoporosis-attributable fractures for Canada based on newly available home care and long-term care (LTC) data. METHODS: Multiple national databases were used for the fiscal-year ending March 31, 2011 (FY 2010/2011) for acute institutional care, emergency visits, day surgery, secondary admissions for rehabilitation, and complex continuing care, as well as national dispensing data for osteoporosis medications. Gaps in national data were supplemented by provincial and community survey data. Osteoporosis-attributable fractures for Canadians age 50+ were identified by ICD-10-CA codes. Costs were expressed in 2014 dollars. RESULTS: In FY 2010/2011, the number of osteoporosis-attributable fractures was 131,443 resulting in 64,884 acute care admissions and 983,074 acute hospital days. Acute care costs were $1.5 billion, an 18 % increase since 2008. The cost of LTC was 33.4 times the previous estimate ($31 million versus $1.03 billion) because of improved data capture. The cost for rehabilitation and secondary admissions increased 3.4 fold, while drug costs decreased 19 %. The overall cost of osteoporosis was over $4.6 billion, an increase of 83 % from the 2008 estimate. CONCLUSION: Since the 2008 estimate, new Canadian data on home care and LTC are available which provided a better estimate of the burden of osteoporosis in Canada. This suggests that our previous estimates were seriously underestimated.

Polymorphisms in the canine glucocorticoid receptor alpha gene (NR3C1α).

Corticosteroids are one of the most extensively used class of therapeutic agents in dogs. In human patients, response to corticosteroid therapy has been correlated with the presence of certain polymorphisms of the glucocorticoid receptor gene (NR3C1). Depending on the polymorphism present, patients may show either increased sensitivity to glucocorticoid-induced adverse effects or resistance to their therapeutic effects. Because response to corticosteroid therapy in dogs can also be variable and unpredictable, we hypothesized that genetic variability exists in the canine NR3C1 gene. The aim of this study was to sequence the coding regions of the canine NR3C1 gene in a representative sample of dogs. Samples from 97 dogs from four previously identified genetic groupings of domestic breeds (Asian/Ancient, Herding, Hunting, and Mastiff) were sequenced and evaluated. Four exons contained polymorphisms and four exons showed no variation from the reference sequence. A total of six single nucleotide polymorphisms (SNPs) were identified including four synonymous SNPs and two nonsynonymous SNPs (c.811A>T and c.2111T>C). No dogs were homozygous for either variant allele, while 23 dogs were heterozygous for the c.811A>T allele and 2 were heterozygous for c.2111T>C allele. The amino acid changes caused by c.811A>T (serine to cysteine) and c.2111T>C (isoleucine to threonine) were both predicted by in silico analysis to be 'probably damaging' to structure and function of the resulting protein. We conclude that NR3C1 polymorphisms occur in dogs and may cause individual variation in response to corticosteroid therapy.

Identification of a nonsense mutation in feline ABCB1.

The aim of this study was to sequence all exons of the ABCB1 (MDR1) gene in cats that had experienced adverse reactions to P-glycoprotein substrate drugs (phenotyped cats). Eight phenotyped cats were included in the study consisting of eight cats that experienced central nervous system toxicosis after receiving ivermectin (n = 2), a combination product containing moxidectin and imidacloprid (n = 3), a combination product containing praziquantel and emodepside (n = 1) or selamectin (n = 2), and 1 cat that received the product containing praziquantel and emodepside but did not experience toxicity (n = 1). Fifteen exons contained polymorphisms and twelve exons showed no variation from the reference sequence. The most significant finding was a nonsense mutation (ABCB11930_1931del TC) in one of the ivermectin-treated cats. This cat was homozygous for the deletion mutation. All of the other phenotyped cats were homozygous for the wild-type allele. However, 14 missense mutations were identified in one or more phenotyped cats. ABCB11930_1931del TC was also identified in four nonphenotyped cats (one homozygous and three heterozygous for the mutant allele). Cats affected by ABCB11930_1931del TC would be expected to have a similar phenotype as dogs with the previously characterized ABCB1-1Δ mutation.

Platelet reactivity changes significantly throughout all trimesters of pregnancy compared with the nonpregnant state: a prospective study.

OBJECTIVE: Platelets play an important role in the pathophysiology of uteroplacental disease and platelet reactivity may be an important marker of uteroplacental disease activity. However, platelet reactivity has not been evaluated comprehensively in normal pregnancy. We sought to evaluate platelet reactivity using a number of agonists at defined time points in pregnancy using a novel platelet assay and compare these with a nonpregnant cohort. DESIGN: Prospective longitudinal study. SETTING: Outpatient department of a large tertiary referral centre. SAMPLE: Eighty participants with 30 nonpregnant women and 50 pregnant women assessed longitudinally. METHODS: This was a prospective cohort study performed longitudinally throughout uncomplicated singleton pregnancies with participants recruited before 15 weeks of gestation. They were controlled for a number of factors known to affect platelet reactivity. Blood samples were obtained in each trimester. Thirty nonpregnant healthy female volunteers also had a platelet assay performed. A modification of standard light transmission aggregometry was used to assess platelet function, with light absorbance measured following the addition of five different agonists at submaximal concentrations. Dose-response curves were plotted for each agonist for the nonpregnant cohort and in each trimester for the pregnant cohort. MAIN OUTCOME MEASURES: Dose-response curves and median effective concentration. RESULTS: When compared with the nonpregnant controls a significant reduction was demonstrated in platelet reactivity to collagen during the first trimester of pregnancy (P < 0.0001). Platelet aggregation increased significantly from the first to third trimesters in response to collagen and arachidonic acid. CONCLUSION: Platelet reactivity varies according to pregnancy state, gestational age and agonist. The finding that platelet reactivity is reduced in the first trimester of pregnancy may be useful for the interpretation of further studies examining the role of platelet reactivity in the first trimester of pregnancies that develop uteroplacental disease.

Hip pain and cauda equina syndrome.

Acute cauda equina syndrome secondary to a spinal epidural abscess as a result of a psoas abscess is very uncommon. We report the case of a 64-year old with a 6-day history of left hip pain, which progressively worsened until she presented to the emergency department with systemic infective symptoms and classical acute cauda equina syndrome. A good clinical outcome was achieved by urgent posterior decompression, followed by CT-guided drainage of the psoas abscess and appropriate antibiotic treatment.

Scoliosis secondary to an unusual rib lesion.

Tumours of the chest wall are uncommon and are usually malignant. A bone haemangioma is a rare benign vascular neoplasm, which more commonly occurs in middle-aged patients. We present the case of a scoliosis caused by a rib haemangioma in an adolescent male. Other causes of scoliosis secondary to rib lesions are discussed.

Recent advances in liver transplantation.

Liver transplant is a life-saving treatment with 1-year and 5-year survival rates of 90% and 70%, respectively. However, organ demand continues to exceed supply, such that many patients will die waiting for an available organ. This article reviews for the general gastroenterologist the latest developments in the field to reduce waiting list mortality and maximise utilisation of available organs. The main areas covered include legislative changes in organ donation and the new 'opt-out' systems being rolled out in the UK, normothermic machine perfusion to optimise marginal grafts, a new national allocation system to maximise benefit from each organ and developments in patient 'prehabilitation' before listing. Current areas of research interest, such as immunosuppression withdrawal, are also summarised.

Neuronal peptide release is limited by secretory granule mobility.

Neuropeptides are slowly released from a limited pool of secretory granules. To visualize this process, GFP-tagged preproatrial natriuretic factor (ANF) was expressed in nerve growth factor-treated PC12 cells. Biochemical and microfluorimetric experiments demonstrate that proANF-EGFP is packaged in granules that accumulate at neurite endings and is released in a Ca2+-dependent manner by secretagogs. Confocal microscopy shows that secretion is associated with depletion of granules distributed throughout the terminal. Fluorescence recovery after photobleaching and time-lapse particle tracking reveal that only a subpopulation of cytoplasmic secretory granules, similar in size to the releasable pool, can move quickly enough (D = 6 x 10(-11) cm2/s) to support release. Therefore, sustained secretory responses are limited by the number of mobile granules and their slow rate of diffusion.

Comparison of chemotherapeutic drug resistance in cells transfected with canine ABCG2 or feline ABCG2.

ABCG2 (ATP binding cassette subfamily G, member 2) mediates resistance to a variety of cytotoxic agents. Although human ABCG2 is well characterized, the function of canine ABCG2 has not been studied previously. Feline ABCG2 has an amino acid substitution in the adenosine triphosphate-binding domain that decreases its transport capacity relative to human ABCG2. Our goal was to compare canine ABCG2-mediated chemotherapeutic drug resistance to feline ABCG2-mediated chemotherapeutic drug resistance. HEK-293 cells stably transfected with plasmid containing canine ABCG2, feline ABCG2 or no ABCG2 were exposed to carboplatin, doxorubicin, mitoxantrone, toceranib or vincristine, and cell survival was subsequently determined. Canine ABCG2 conferred a greater degree of chemotherapy resistance than feline ABCG2 for mitoxantrone. Neither canine nor feline ABCG2 conferred resistance to doxorubicin, vincristine or toceranib. Canine, but not feline, ABCG2 conferred resistance to carboplatin, a drug that is not reported to be a substrate for ABCG2 in other species.

Regenerate bone fracture rate following femoral lengthening in paediatric patients.

PURPOSE: Femoral lengthening using a circular or mono-lateral frame is a commonly used technique. Fracture at the site of the regenerate bone is a major concern especially following removal of the external fixator. This aim of this study was to assess the rate of fracture of the regenerate bone in this single surgeon series of paediatric patients and determine potential risk factors. METHODS: Retrospective review of all the femoral lengthening performed by the senior author was performed. The medical and physiotherapy notes were reviewed. The gender, age at time of surgery, disease aetiology, total days in the external fixator and length of the new regenerate bone were recorded. Patients who sustained a regenerate fracture were identified. RESULTS: A total of 176 femoral lengthening procedures were performed on 108 patients. Eight regenerate fractures occurred in seven patients (4.5%). The mechanism of injury was a fall in five cases and during physiotherapy in three cases. The regenerate fracture occurred a median number of nine days following removal of frame. There was no significant difference between gender, age at time of surgery, total time in external fixator between those who sustained a regenerate fracture and those patients who did not. A significant difference was noted between the amount of lengthening between the 'regenerate fracture group' and the 'no fracture group' (50 mm vs 38 mm, respectively; p = 0.029). There was no association between disease aetiology and risk of regenerate fracture. CONCLUSIONS: Femoral lengthening of more than 50 mm increases the risk of a fracture at the regenerate site regardless of the disease aetiology. We recommend avoidance of aggressive physiotherapy for the initial four weeks following external fixator removal.