Real-world bone turnover marker use: impact on treatment decisions and fracture.

The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice. INTRODUCTION: The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database. METHODS: Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture. RESULTS: Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88). CONCLUSION: In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.

A systematic review and meta-analysis of factors associated with anthelmintic resistance in sheep.

BACKGROUND: Anthelmintic drugs have been widely used in sheep as a cost-effective means for gastro-intestinal nematode (GIN) control. However, growing anthelmintic resistance (AHR) has created a compelling need to identify evidence-based management recommendations that reduce the risk of further development and impact of AHR. OBJECTIVE: To identify, critically assess, and synthesize available data from primary research on factors associated with AHR in sheep. METHODS: Publications reporting original observational or experimental research on selected factors associated with AHR in sheep GINs and published after 1974, were identified through two processes. Three electronic databases (PubMed, Agricola, CAB) and Web of Science (a collection of databases) were searched for potentially relevant publications. Additional publications were identified through consultation with experts, manual search of references of included publications and conference proceedings, and information solicited from small ruminant practitioner list-serves. Two independent investigators screened abstracts for relevance. Relevant publications were assessed for risk of systematic bias. Where sufficient data were available, random-effects Meta-Analyses (MAs) were performed to estimate the pooled Odds Ratio (OR) and 95% Confidence Intervals (CIs) of AHR for factors reported in ≥2 publications. RESULTS: Of the 1712 abstracts screened for eligibility, 131 were deemed relevant for full publication review. Thirty publications describing 25 individual studies (15 observational studies, 7 challenge trials, and 3 controlled trials) were included in the qualitative synthesis and assessed for systematic bias. Unclear (i.e. not reported, or unable to assess) or high risk of selection bias and confounding bias was found in 93% (14/15) and 60% (9/15) of the observational studies, respectively, while unclear risk of selection bias was identified in all of the trials. Ten independent studies were included in the quantitative synthesis, and MAs were performed for five factors. Only high frequency of treatment was a significant risk factor (OR=4.39; 95% CI=1.59, 12.14), while the remaining 4 variables were marginally significant: mixed-species grazing (OR=1.63; 95% CI=0.66, 4.07); flock size (OR=1.02; 95% CI=0.97, 1.07); use of long-acting drug formulations (OR=2.85; 95% CI=0.79, 10.24); and drench-and-shift pasture management (OR=4.08; 95% CI=0.75, 22.16). CONCLUSIONS: While there is abundant literature on the topic of AHR in sheep GINs, few studies have explicitly investigated the association between putative risk or protective factors and AHR. Consequently, several of the current recommendations on parasite management are not evidence-based. Moreover, many of the studies included in this review had a high or unclear risk of systematic bias, highlighting the need to improve study design and/or reporting of future research carried out in this field.

A comparison of the patient and surgeon opinion on the long-term aesthetic outcome of reduction mammaplasty: have we improved over 15 years?

In 1996 we published a study evaluating the difference between patient and surgeon opinion on the aesthetic outcome of reduction mammaplasty (see Ref. 1). The patients rated the aesthetic outcome of their surgery as significantly higher than the consultant panel. The surgical panel suggested scope for improvement. Areas of dissatisfaction were poor scarring, high placement of the nipple areola complex and high rates of revision surgery. Fifteen years on, the same team has regrouped to repeat this assessment. In 1996 the consultants scored their own patient results. In 2011 they graded the results of their former trainee who has modified her operative technique to address aesthetic problems highlighted in the first study. Forty-four patients attended a review clinic at least one year post reduction mammaplasty. Patient scored their satisfaction using the original questionnaire employed in 1996. The cohort were photographed and their images graded blindly by the original surgical panel. Statistical analysis was performed by the original statistician. The patients graded aesthetic aspects of body harmony, breast mound appearance, nipple areolar complex appearance and post-operative scarring significantly more positively (p<0.01) than both the 1996 patient cohort and surgical panel. The consultant panel showed a trend for more positive grades for all aesthetic features assessed versus their previous views but this was only significant for breast mound symmetry. They expressed that there was a decrease in post-operative breast ptosis (p<0.04) and improvement in the nipple areolar complex position (p=0.02). The rate of revision surgery has decreased from 53% to 16% between the studies. In keeping with clinical audit, outcomes have been assessed and modifications implemented to address aesthetic concerns. Assessment of outcomes following the modifications demonstrates a trend for increased patient and surgeon satisfaction. Patient satisfaction however still exceeds that of the surgeons.

A systematic review and meta-analysis of phase I inactivated vaccines to reduce shedding of Coxiella burnetii from sheep and goats from routes of public health importance.

Q fever in humans and coxiellosis in livestock are both caused by Coxiella burnetii. The public health importance of vaccination against C. burnetii shedding from sheep and goats was evaluated using systematic review and meta-analysis to provide evidence for policy direction to prevent potential zoonotic spread. Publications reporting shedding of C. burnetii in vaginal and uterine secretions, milk, placenta and faeces were included. A single observational (one goat) and seven experimental (four goat and three sheep) vaccine studies were included in the review. No relevant publications on other interventions were identified. Random effects meta-analyses were performed for the risk of shedding in individuals in the control and vaccinated groups and for the mean difference in the level of bacterial shedding in sheep and goats stratified by age and previous exposure status. Limited data were available for further analytic evaluation. From the pooled analysis, an inactivated phase I vaccine significantly reduced the risk of shedding from uterine (RR = 0.10; 95%CI 0.05-0.20) secretions in previously sensitized goats. Individual studies reported significant risk reduction in milk (RR = 0.03; 95%CI 0.01-0.26), vaginal secretions (RR = 0.40; 95%CI 0.22-0.75) and faeces (RR = 0.79; 95%CI 0.63-0.97) from naïve goats. The pooled mean levels of bacteria shed from placental [mean difference (MD = -5.24 Log10 ; 95%CI -6.75 to -3.7)] and vaginal (MD = -1.78 Log10 ; 95%CI -2.19 to -1.38) routes were significantly decreased in vaccinated naïve goats compared with controls. Shedding through all other routes from vaccinated goats was not significantly different than shedding from control goats. No effect of vaccination was found on the risk of shedding or the mean level of shedding in vaccinated sheep compared with control sheep. Our conclusions are based on a limited amount of data with variable risk of systematic error.

The effectiveness of Coxiella burnetii vaccines in occupationally exposed populations: a systematic review and meta-analysis.

To estimate the effect of vaccination in preventing acute Q fever in individuals occupationally exposed to Coxiella burnetii, a systematic review and meta-analysis were undertaken in controlled trials and observational studies. Publications were obtained through a scoping study of English and non-English articles, and those reporting a commercially licensed or licensable vaccine compared with an unvaccinated or placebo control group were included in the review. Two authors performed independent assessment of risk of systematic error and data extraction. One controlled trial and five cohort publications met the inclusion criteria. All trials used a Henzerling phase I vaccine. A random-effects meta-analysis estimated significant protection in abattoir workers (RR = 0.07; 95% confidence interval [CI] 0.02-0.22) compared with the control individuals. In individuals with rare or sporadic contact with the abattoir, a significant benefit of vaccination was also found (RR = 0.06; 95% CI 0-0.93). Overall, the vaccine effectively prevented acute Q fever in individuals responsible for handling animals or their products and those working in the abattoir but not directly exposed to animals (RR = 0.06; 95% CI 0.02-0.18). Caution must be taken when interpreting the effect of C. burnetii vaccination as significant heterogeneity amongst publications was observed. A meta-regression found no significant univariate associations. This may reflect the uncertainty provided by reported data in the cohort publications. Potential systematic biases were present in the publications, and evidence included may not be sufficiently robust to extrapolate the effect of vaccination on occupationally exposed groups beyond the population of abattoir employees in Australia where all included studies occurred.

Effect of surgical technique on radiographic fusion of the anconeus in the treatment of ununited anconeal process.

OBJECTIVES: The aim of this study was to determine if internal fixation of the anconeus combined with a proximal ulnar osteotomy was more likely to result in fusion of the anconeus to the ulna compared with a proximal ulnar osteotomy alone. METHODS: A total of 12 orthopaedic referral clinics reviewed their clinical databases for cases of ununited anconeal process. Demographic and clinical parameters were collected along with radiographic follow-up at a minimum of four weeks. Cases treated with proximal ulnar osteotomy alone were compared with those treated with proximal ulnar osteotomy + internal fixation. Both groups were compared for background and disease variables. We tested for an association between treatment method and whether radiographic anconeal union had occurred. RESULTS: A total of 47 elbows (44 dogs) were identified. Of these, 28 cases (average age 7.6 months) were treated with proximal ulnar osteotomy (of which eight were stabilised with an intramedullary pin) alone. Nineteen cases (average age 7.1 months) were treated with proximal ulnar osteotomy + internal fixation. The two groups were not significantly different in age (P=0.638, Mann-Whitney U test). Fourteen of 28 cases with proximal ulnar osteotomy alone displayed anconeal union at follow-up compared with 16 of 19 cases of proximal ulnar osteotomy + internal fixation, and this difference was statistically significant (P=0.029, Fisher's exact test). CLINICAL SIGNIFICANCE: These data suggest that use of a lag screw to stabilise and compress the ununited anconeal process in addition to proximal ulnar osteotomy produces a better radiographic outcome. It is argued that radiographic union of the anconeus is likely to be associated with better long-term clinical outcome but further studies are required to confirm this.

Evaluation of the impact of breast cancer screening in South Australia.

BACKGROUND: In 1989 BreastScreen SA started screening for breast cancer in South Australia. METHODS: The programme concentrated on women between the ages of 50 and 69, using a 24-month screening interval and a joint method of mammography, clinical examination and self-detection. RESULTS: This paper is a summary of our efforts to provide an assessment of the impact of the screening programme in terms of additional survival time past the age of first detection of the disease. DISCUSSION: The concept of benchmarks is introduced, and the survival advantages for screened women is measured from these benchmarks. CONCLUSION: The women in the BreastScreen SA service, who had primary breast tumours, had an estimated additional survival advantage of 2.6 years. Some statistical modelling allowed us to extrapolate to other screening designs.

A subset polynomial neural networks approach for breast cancer diagnosis.

Breast cancer is a very common and serious cancer for women that is diagnosed in one of every eight Australian women before the age of 85. The conventional method of breast cancer diagnosis is mammography. However, mammography has been reported to have poor diagnostic capability. In this paper we have used subset polynomial neural network techniques in conjunction with fine needle aspiration cytology to undertake this difficult task of predicting breast cancer. The successful findings indicate that adoption of NNs is likely to lead to increased survival of women with breast cancer, improved electronic healthcare, and enhanced quality of life.

Home oxygen therapy and cigarette smoking: a dangerous practice.

Oxygen as a therapeutic agent is an important form of home therapy for hypoxic chronic obstructive pulmonary disease (COPD) and improved survival has been demonstrated in hypoxic COPD patients receiving continuous oxygen. However, some patients, despite dissuasion, continue to smoke and we describe the case of a patient on home oxygen who sustained a partial-thickness facial flash burn whilst engaged in this habit. A review is made of the literature, as also a comparison of all discovered cases of burns in home oxygen users, followed by a discussion of the implications of this potentially hazardous form of therapy.

A case report of cutis laxa in one of identical twins.

A 29-year-old man with cutis laxa presented requesting surgery to improve his appearance. The patient had an unaffected identical twin brother which allowed us to compare how he had changed over the years in relation to his sibling and this also provided us with a gold standard for any surgery performed. The patient underwent staged surgery including upper lid blepharoplasties and two facelifts.

Identification of G protein-coupled, inward rectifier potassium channel gene products from the rat anterior pituitary gland.

Dopamine (DA) is a physiological regulator of PRL secretion, exerting tonic inhibitory control. DA activates an inward rectifier K(+) (IRK) channel in rat lactotropes, causing membrane hyperpolarization and inhibition of Ca(2+)-dependent action potentials. Both the activation of this effector K(+) channel and the inhibition of PRL release are mediated by D(2)-type receptor activation and pertussis toxin- sensitive G proteins. To study the molecular basis of this physiologically relevant channel, a homology-based PCR approach was employed to identify members of the IRK channel family expressed in the anterior pituitary gland. Nondegenerate primers corresponding to regions specific for IRK channels known to be G protein activated (GIRKs; gene subfamily Kir 3.0) were synthesized and used in the PCR with reverse transcribed female rat anterior pituitary messenger RNA as the template. PCR products of predicted sizes for Kir 3.1, 3.2, and 3.4 were consistently observed by ethidium bromide staining after 16 amplification cycles. The identities of the products were confirmed by subcloning and sequencing. Expression of each of these gene products in anterior pituitary was confirmed by Northern blot analysis. Functional analysis of the GIRK proteins was performed in the heterologous expression system, Xenopus laevis oocytes. Macroscopic K(+) currents were examined in oocytes injected with different combinations of Kir 3.0 complementary RNA (cRNA) and G protein subunit (beta(1)gamma(2)) cRNA. The current-voltage relationships demonstrated strong inward rectification for each individual and pairwise combination of GIRK channel subunits. Oocytes coinjected with any pair of GIRK subunit cRNA exhibited significantly larger inward K(+) currents than oocytes injected with only one GIRK channel subtype. Ligand-dependent activation of only one of the GIRK combinations (GIRK1 and GIRK4) was observed when channel subunits were coexpressed with the D(2) receptor in Xenopus oocytes. Dose-response data fit to a Michaelis-Menten equation gave an apparent K(d) similar to that for DA binding in anterior pituitary tissue. GIRK1 and GIRK4 proteins were coimmunoprecipitated from anterior pituitary lysates, confirming the presence of native GIRK1/GIRK4 oligomers in this tissue. These data indicate that GIRK1 and GIRK4 are excellent candidate subunits for the D(2)-activated, G protein-gated channel in pituitary lactotropes, where they play a critical role in excitation-secretion coupling.

Convergence criteria for scattering models of ultrasonic wave propagation in suspensions of particles.

Scattering models used to simulate the attenuation and phase velocity of an ultrasonic wave propagating through a suspension of particles involve the summation of an infinite series of partial waves. The accuracy of computation is influenced by the number of terms included in the harmonic series, and the number of terms required depends upon the scatterer size compared with wavelength. It is shown that the errors in modelled attenuation and phase velocity resulting from premature truncation can be significant when modelling higher values of particle diameter-frequency product. A useful and simple heuristic is presented, in which the number of terms in the summation of the infinite series needed for satisfactory convergence to a final value is a function of the particle diameter-frequency product and of the compressive wave velocity in the continuous phase.

Estimating cohort health expectancies from cross-sectional surveys of disability.

A life history can be regarded as a random process that evolves with age through various states of health before terminating with absorption into the state of death. Health expectancies are the occupation times of the non-absorbing states and their estimation is of interest. A continuing major problem has been the lack of satisfactory longitudinal data on which to base estimates and as a result standard inferential techniques may not be relevant. Supposing only cross-sectional data available, we propose a method that is generally applicable and first estimates a logistic parametrization of the probabilities of the various states. A large sample approximation is obtained for the distribution of age specific log (odds). Parameters are estimated by weighted least squares, and this in turn leads to estimates of cohort health expectancies. A result of Liang and Zeger is used to find standard errors. The method is illustrated by application to Australian data from the health surveys of 1981, 1988 and 1993.

Oxo-piperazine derivatives of N-arylpiperazinones as inhibitors of farnesyltransferase.

The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.

Synthesis of conformationally constrained 5,6,7, 8-Tetrahydroimidazo[1,5-a]pyridine inhibitors of farnesyltransferase.

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.

Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults.

PRO 542 (CD4-IgG2) is a recombinant antibody-like fusion protein wherein the Fv portions of both the heavy and light chains of human IgG2 have been replaced with the D1D2 domains of human CD4. Unlike monovalent and divalent CD4-based proteins, tetravalent PRO 542 potently neutralizes diverse primary human immunodeficiency virus (HIV) type 1 isolates. In this phase 1 study, the first evaluation of this compound in humans, HIV-infected adults were treated with a single intravenous infusion of PRO 542 at doses of 0.2-10 mg/kg. PRO 542 was well tolerated, and no dose-limiting toxicities were identified. Area under the concentration-time curve, and peak serum concentrations increased linearly with dose, and a terminal serum half-life of 3-4 days was observed. No patient developed antibodies to PRO 542. Preliminary evidence of antiviral activity was observed as reductions in both plasma HIV RNA and plasma viremia. Sustained antiviral effects may be achieved with repeat dosing with PRO 542.

The analysis of group truncated binary data with random effects: injury severity in motor vehicle accidents.

The analysis of group truncated binary data has been previously considered by O'Neill and Barry (1995b, Biometrics 51, 533-541), where the analysis assumed that responses within each group were independent. In this paper, we consider the analysis of such data when there is group-level heterogeneity. A generalized linear mixed model is hypothesized to model the response and maximum likelihood estimates are derived for the truncated case. A score test is derived to test for heterogeneity. Finally, the method is applied to a set of traffic accident data.

Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.

For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Although these data support the further development of FTIs, it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers. Moreover, Ki-RasB binds more tightly to FPTase than either Ha- or N-Ras, and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing. Given the unique biochemical and biological features of Ki-RasB, it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein. We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V) under the control of the MMTV enhancer/promoter. The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detected in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity. Although FPTase activity was inhibited in tumors from the treated mice, unprocessed Ki-RasB was not detected. These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model, Ki-Ras may not be the sole mediator of the biological effects of the FTI.