Inflammatory Markers and Risk of Hip Fracture in Older White Women: The Study of Osteoporotic Fractures †

Abstract Hip fractures are the most devastating consequence of osteoporosis and impact 1 in 6 white women leading to a 2-3 fold increased mortality risk in the first year. Despite evidence of inflammatory markers in the pathogenesis of osteoporosis, few studies have examined their effect on hip fracture. To determine if high levels of inflammation increase hip fracture risk and explore mediation pathways, a case-cohort design nested in a cohort of 4709 white women from the Study of Osteoporotic Fractures was used. A random sample of 1171 women was selected as the subcohort (mean age 80.1 ± 4.2 years) plus the first 300 women with incident hip fracture. Inflammatory markers interleukin-6 (IL-6) and soluble receptors (SR) for IL-6 (IL-6 SR) and tumor necrosis factor (TNF SR1 and TNF SR2) were measured and participants were followed for a median (interquartile range) of 6.3 (3.7, 6.9) years. In multivariable models, the hazard ratio (HR) of hip fracture for women in the highest inflammatory marker level (quartile 4) was 1.64 (95% confidence interval [CI], 1.09-2.48, p trend=0.03) for IL-6 and 2.05 (95% CI, 1.35-3.12, p trend <0.01) for TNF SR1 when compared with women in the lowest level (quartile 1). Among women with 2 and 3-4 inflammatory markers in the highest quartile, the HR of hip fracture was 1.51 (95% CI, 1.07-2.14) and 1.42 (95% CI, 0.87-2.31) compared with women with 0-1 marker(s) in the highest quartile (p trend = 0.03). After individually adjusting for 7 potential mediators, cystatin-C (a biomarker of renal function) and bone mineral density (BMD) attenuated HRs among women with the highest inflammatory burden by 20% and 15%, respectively, suggesting a potential mediating role. Older white women with high inflammatory burden are at increased risk of hip fracture in part due to poor renal function and low BMD

Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib, a COX-2 selective inhibitor, in osteoarthritis (OA) patients. METHODS: A double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee. The base study was 14 weeks in duration and consisted of 2 parts; in Part I (6 weeks), patients were allocated to once daily oral etoricoxib 5, 10, 30, 60, 90 mg or placebo. In Part II (8 weeks); the placebo, etoricoxib 5 and 10 mg groups were reallocated to etoricoxib 30, 60, or 90 mg qd or diclofenac 50 mg t.i.d. Treatment was continued for consecutive 12 and 26 week extensions. Primary efficacy endpoints were the WOMAC VA 3.0 pain subscale and investigator global assessment of disease status. Safety and tolerability were assessed by collecting adverse events throughout the study. RESULTS: Compared with placebo, the etoricoxib groups displayed significant (p < 0.05), dose-dependent efficacy for all primary endpoints in Part I; efficacy was maintained throughout the 52 weeks of the study. During the 46-week active-comparator controlled period, the etoricoxib groups demonstrated clinical efficacy that was similar to that of diclofenac 150 mg and was generally well tolerated, with a lower incidence of gastrointestinal (GI) nuisance symptoms compared with diclofenac (13.1, 14.7, and 13.5% for etoricoxib 30, 60, and 90 mg, respectively compared with 22.5% for diclofenac). CONCLUSION: In this extension study, etoricoxib, at doses ranging from 30 to 90 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment. Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated

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ABSTRACT. Objective. To assess the overall safety, including rare events, of intravenous (IV) abatacept treatment in rheumatoid arthritis (RA). Methods. Data from 8 clinical trials of IV abatacept in RA were pooled. Safety events were assessed during the short-term (duration ≤ 12 months) and cumulative (short-term plus longterm extensions) abatacept treatment periods. Incidence rates per 100 patient-years were calculated. Standardized incidence ratios (SIR) for hospitalized infections and malignancies were compared with external RA cohorts and, for malignancies, with the US general population. Results. There were 3173 IV abatacept-treated patients with 2331 patient-years of exposure in the short-term periods, and 4149 IV abatacept-treated patients with 12,132 patient-years of exposure in the cumulative period. Incidence rates for serious infections were low and consistent over time (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA patient cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept-and placebo-treated patients during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). SIR of some tissue-specific malignancies (e.g., colorectal and breast) in the cumulative period tended to be lower, while others (lymphoma and lung) tended to be higher, compared with the general population; however, incidence rates were comparable with RA cohorts. Autoimmune events were rare and infusion reactions uncommon. Conclusion. Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, malignancies, and autoimmune events. Leuven, Leuven, Belgium; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Bristol-Myers Squibb, Princeton, New Jersey

Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.

Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF-β signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR-140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa-miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa-miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression.Peer reviewedFinal Published versio

A simulation study on the effects of neuronal ensemble properties on decoding algorithms for intracortical brain-machine interfaces

Background: Intracortical brain-machine interfaces (BMIs) harness movement information by sensing neuronal activities using chronic microelectrode implants to restore lost functions to patients with paralysis. However, neuronal signals often vary over time, even within a day, forcing one to rebuild a BMI every time they operate it. The term &quot;rebuild&quot; means overall procedures for operating a BMI, such as decoder selection, decoder training, and decoder testing. It gives rise to a practical issue of what decoder should be built for a given neuronal ensemble. This study aims to address it by exploring how decoders&apos; performance varies with the neuronal properties. To extensively explore a range of neuronal properties, we conduct a simulation study. Methods: Focusing on movement direction, we examine several basic neuronal properties, including the signal-to-noise ratio of neurons, the proportion of well-tuned neurons, the uniformity of their preferred directions (PDs), and the non-stationarity of PDs. We investigate the performance of three popular BMI decoders: Kalman filter, optimal linear estimator, and population vector algorithm. Results: Our simulation results showed that decoding performance of all the decoders was affected more by the proportion of well-tuned neurons that their uniformity. Conclusions: Our study suggests a simulated scenario of how to choose a decoder for intracortical BMIs in various neuronal conditions

Cryptic multiple hypotheses testing in linear models: overestimated effect sizes and the winner's curse

Fitting generalised linear models (GLMs) with more than one predictor has become the standard method of analysis in evolutionary and behavioural research. Often, GLMs are used for exploratory data analysis, where one starts with a complex full model including interaction terms and then simplifies by removing non-significant terms. While this approach can be useful, it is problematic if significant effects are interpreted as if they arose from a single a priori hypothesis test. This is because model selection involves cryptic multiple hypothesis testing, a fact that has only rarely been acknowledged or quantified. We show that the probability of finding at least one ‘significant’ effect is high, even if all null hypotheses are true (e.g. 40% when starting with four predictors and their two-way interactions). This probability is close to theoretical expectations when the sample size (N) is large relative to the number of predictors including interactions (k). In contrast, type I error rates strongly exceed even those expectations when model simplification is applied to models that are over-fitted before simplification (low N/k ratio). The increase in false-positive results arises primarily from an overestimation of effect sizes among significant predictors, leading to upward-biased effect sizes that often cannot be reproduced in follow-up studies (‘the winner's curse’). Despite having their own problems, full model tests and P value adjustments can be used as a guide to how frequently type I errors arise by sampling variation alone. We favour the presentation of full models, since they best reflect the range of predictors investigated and ensure a balanced representation also of non-significant results

Canadian physiotherapists' views on certification, specialisation, extended role practice, and entry-level training in rheumatology

<p>Abstract</p> <p>Background</p> <p>Since the last decade there has been a gradual change of boundaries of health professions in providing arthritis care. In Canada, some facilities have begun to adopt new arthritis care models, some of which involve physiotherapists (PT) working in extended roles. However, little is known about PTs' interests in these new roles. The primary objective of this survey was to determine the interests among orthopaedic physiotherapists (PTs) in being a certified arthritis therapist, a PT specialized in arthritis, or an extended scope practitioner in rheumatology, and to explore the associated factors, including the coverage of arthritis content in the entry-level physiotherapy training.</p> <p>Methods</p> <p>Six hundred PTs practicing in orthopaedics in Canada were randomly selected to receive a postal survey. The questionnaire covered areas related to clinical practice, perceptions of rheumatology training received, and attitudes toward PT roles in arthritis care. Logistic regression models were developed to explore the associations between PTs' interests in pursuing each of the three extended scope practice designations and the personal/professional/attitudinal variables.</p> <p>Results</p> <p>We received 286 questionnaires (response rate = 47.7%); 258 contained usable data. The average length of time in practice was 15.4 years (SD = 10.4). About 1 in 4 PTs agreed that they were interested in assuming advanced practice roles (being a certified arthritis therapist = 28.9%, being a PT specialized in rheumatology = 23.3%, being a PT practitioner = 20.9%). Having a caseload of ≥ 40% in arthritis, having a positive attitude toward advanced practice roles in arthritis care and toward the formal credentialing process, and recognizing the difference between certification and specialisation were associated with an interest in pursing advanced practice roles.</p> <p>Conclusion</p> <p>Orthopaedic PTs in Canada indicated a fair level of interest in pursuing certification, specialisation and extended scope practice roles in arthritis care. Future research should focus on the effectiveness and cost-effectiveness of the emerging health service delivery models involving certified, specialized or extended scope practice PTs in the management of arthritis.</p

Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215

Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas xenografted into nude mice. High affinity binding of AN-215 to U-87MG tumours was characterised by an IC50 value of 4.0±0.1 nM, as determined by radioreceptor assays. mRNA analyses revealed the presence of mRNA for BN receptor subtypes 1 and 2. Treatment with AN-215 significantly (P<0.05) extended tumour doubling time from 4.54±0.2 days to 8.18±1.8 days and inhibited tumour growth as demonstrated by a 69.6% reduction in final tumour volume (P<0.001) and a 64.6% decrease in tumour weight as compared to controls. Cytotoxic radical AN-201 at the same dose was ineffective. The antitumour effect of AN-215 could be blocked by pretreatment with an excess of a bombesin antagonist, indicating that the action of this cytotoxic analogue is receptor-mediated. Our results suggest that patients with inoperable brain tumours such as malignant gliomas may benefit from targeted chemotherapy based on cytotoxic bombesin analogue AN-215

Temporal estimation with two moving objects: overt and covert pursuit

The current study examined temporal estimation in a prediction motion task where participants were cued to overtly pursue one of two moving objects, which could either arrive first, i.e., shortest [time to contact (TTC)] or second (i.e., longest TTC) after a period of occlusion. Participants were instructed to estimate TTC of the first-arriving object only, thus making it necessary to overtly pursue the cued object while at the same time covertly pursuing the other (non-cued) object. A control (baseline) condition was also included in which participants had to estimate TTC of a single, overtly pursued object. Results showed that participants were able to estimate the arrival order of the two objects with very high accuracy irrespective of whether they had overtly or covertly pursued the first-arriving object. However, compared to the single-object baseline, participants’ temporal estimation of the covert object was impaired when it arrived 500 ms before the overtly pursued object. In terms of eye movements, participants exhibited significantly more switches in gaze location during occlusion from the cued to the non-cued object but only when the latter arrived first. Still, comparison of trials with and without a switch in gaze location when the non-cued object arrived first indicated no advantage for temporal estimation. Taken together, our results indicate that overt pursuit is sufficient but not necessary for accurate temporal estimation. Covert pursuit can enable representation of a moving object’s trajectory and thereby accurate temporal estimation providing the object moves close to the overt attentional focus