Breed structures in Australian dairy herds.

Breed structures of Australian dairy herds over time were described for a large subset of milk-recording herds. The focus for this study was to describe the use of crossbreeding by dairy farmers, specifically proportions of herds using crossbreeding, whether they were using two-breed or three-breed crossbreeding systems, and how herd-breed structures changed over time. The most common breed structure in Australian milk-recording herds between 2000 and 2013 was two-breed crossbreeding (39% of herd-years). The next most common breed structure was purebred (35%). Over the period studied, the proportion of herds that were purebred decreased, while the proportion of herds that were crossbreeding increased (particularly three-breed crossbreeding herds). Herd-breed structures and changes over time varied with region and with the herd's calving system. There were also considerable changes in breed structure within herds, including herds changing breed structure before reverting back to their original breed structure. These results indicate that breed structures in milk-recording dairy herds in Australia are dynamic, and that farmers have commonly employed crossbreeding strategies.

Operative Management of Perinatal Lumbar Disc Herniation and Cauda Equina Syndrome: A Case Series

Introduction Perinatal lumbar discectomy for lumbar disc herniation or cauda equina syndrome is a rare clinical scenario. This case series outlines the surgical management of this clinical scenario at a national tertiary referral centre over a 10-year period Methods A retrospective review of all females who underwent discectomy / decompression for lumbar disc herniation or cauda equina syndrome in the perinatal period at a national tertiary referral centre for spine surgery over a 10-year period between January 2008 to December 2017. Results 6 cases required surgical intervention. All patients were successfully managed with surgical decompressive procedures and recovered well in the postoperative period without complication. Conclusions The principles of management remain the same in the pregnant and non-pregnant populations, although treatment options are complicated by the desire to avoid risk to the developing foetus. Surgical intervention is safe to both mother and baby and if performed promptly is associated with an excellent functional outcome.

The effect of inoculum source and fluid shear force on the development of in vitro oral multispecies biofilms.

AIMS: Saliva has been previously used as an inoculum for in vitro oral biofilm studies. However, the microbial community profile of saliva is markedly different from hard- and soft-tissue-associated oral biofilms. Here, we investigated the changes in the biofilm architecture and microbial diversity of in vitro oral biofilms developed from saliva, tongue or plaque-derived inocula under different salivary shear forces. METHODS AND RESULTS: Four inoculum types (saliva, bacteria harvested from the tongue, toothbrush and curette-harvested plaque) were collected and pooled. Biofilms (n ≥ 15) were grown for 20 h in cell-free human saliva flowing at three different shear forces. Stained biofilms were imaged using a confocal laser scanning microscope. Biomass, thickness and roughness were determined by image analysis and bacterial community composition analysed using Ion Torrent. All developed biofilms showed a significant reduction in observed diversity compared with their respective original inoculum. Shear force altered biofilm architecture of saliva and curette-collected plaque and community composition of saliva, tongue and curette-harvested plaque. CONCLUSIONS: Different intraoral inocula served as precursors of in vitro oral polymicrobial biofilms which can be influenced by shear. SIGNIFICANCE AND IMPACT OF THE STUDY: Inoculum selection and shear force are key factors to consider when developing multispecies biofilms within in vitro models.

AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes.

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

Effectiveness of 'in-cast' pneumatic intermittent pedal compression for the pre-operative management of closed ankle fractures: a clinical audit.

BACKGROUND: Timing of surgery for ankle fractures is largely dependent on the condition of the surrounding soft-tissues. This study aimed to determine the clinical effectiveness of a pre-operative in-cast artero-venous (AV) impulse device in the management of closed ankle fractures requiring surgery. METHODS: A consecutive series of 64 closed ankle fractures were managed using the AV impulse system prior to surgery. Patients were compared to 73 consecutive closed ankle fractures managed surgically in the same unit immediately prior to the implementation of the AV impulse device study. Outcomes measured were time to surgery, length of hospital stay and surgical site infections. RESULTS: Median length of time to surgery, hospital stay duration and surgical site infections were all significantly reduced in the study group as compared to the control group. CONCLUSIONS: In-cast intermittent AV compression foot pumps in the pre-operative management of closed ankle fractures were associated with earlier surgery, earlier discharge and reduced complications.

Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First-in-Patient Study Designs in Psoriasis.

Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose-ranging designs in the majority of the cases. However, dose-ranging studies in FIP trials offer important design advantages in the form of dose-response (D-R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e58; doi:10.1038/psp.2013.32; published online 24 July 2013.

Preliminary study of the feasibility and accuracy of percutaneous peri-acetabular screw insertion in a porcine model.

The aim of this pilot study was to assess a new method of training for peri-acetabular screw placement under indirect vision using standard C-arm fluoroscopy using a porcine model. Two novice orthopaedic residents placed 72 screws (36 each) about the acetabula of six porcine pelves under C-arm fluoroscopic guidance. Unsatisfactory screw position was noted in 22 of 72, with five instances of screw ingress into the hip joint. All of these cases occurred in the first half of each resident's series. Screw direction and final position improved over subsequent trials. This pilot study demonstrates that surgical simulation techniques are applicable in percutaneous screw fixation. Such an approach could be useful for both residents in training and more experienced surgeons who wish to perform this procedure in cases where it is appropriate.

Delivery of active agents from chewing gum for improved remineralization.

Most surrogate measures of caries were developed to test products containing fluoride, typically at relatively high and closely controlled oral concentrations. However, since the primary mechanism for the remineralization of early enamel caries lesions by chewing gum is through stimulation of saliva, delivering Ca and Pi to the demineralized enamel lesion, established methods may lack the sensitivity to detect the additional benefit of an active agent without the strong remineralizing potential of fluoride. Issues related to the release of active agents from the gum matrix, dilution in the saliva, and limited oral retention time, along with taste, safety, regulatory, and cost concerns, impose further limitations. This paper reviews the efficacy of some active agents used in chewing gum for improved remineralization and includes results from in situ testing of calcium-containing gums, including calcium lactate, tetracalcium phosphate/dicalcium phosphate anhydrous, calcium citrate/encapsulated phosphate, and a calcium lactate/sodium phosphate blend. Despite promising in vitro data from these agents, they did not provide consistently superior results from in situ testing. There is a need to develop better predictive in vitro models for chewing gum, as well as improved sensitivity of in situ models to discriminate relatively small amounts of remineralization against a background of high biological variability.

History of frequent gum chewing is associated with higher unstimulated salivary flow rate and lower caries severity in healthy Chinese adults.

This was a single-center, prospective, cross-sectional study stratified by age and gender with the objective of determining the relationship between gum chewing history, salivary flow, and dental caries severity in adults. We enrolled 191 subjects aged 18-65 years who underwent assessments for gum chewing history, unstimulated salivary flow rate, salivary pH, and caries severity. Unstimulated salivary flow rate tended to decline with increasing age (p = 0.04), and significant differences in unstimulated salivary flow rate were also found for males (0.58 ± 0.32 ml/min) versus females (0.48 ± 0.30 ml/min) (p = 0.02). Weekly gum chewing frequency was greater in younger subjects (p = 0.001) while no age group differences were noted in pieces per day or chewing duration. Gum chewing habits were similar in males and females. A multivariate model demonstrated that only days per week chewing gum (p < 0.001) and gender (p = 0.007) were predictive of unstimulated salivary flow rate (R(2) = 0.40). Mean caries severity scores, assessed via ICDAS II and DMFT, increased with age. In multivariate analysis, age was positively associated with ICDAS (p = 0.001) and days per week chewing gum was negatively associated with ICDAS (p = 0.004), indicating that caries severity increased with age, and that days of chewing provided an inverse effect, with increased days of chewing being associated with decreased severity of caries. Overall, a history of frequent gum chewing is associated with higher unstimulated salivary flow rate and lower caries severity.

Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.

BACKGROUND: Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood. METHODS: Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries. RESULTS: A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers. CONCLUSION: This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.

Causes of prolonged hospital stay following low-energy fracture of the proximal femur: issues of most concern.

Hip fractures are an important cause of morbidity in the elderly and represent a significant proportion of acute orthopaedic admissions. We reviewed a consecutive series of hip fractures presenting to our unit over five years, obtaining demographic and clinical data from patient's medical records. Patients who remained in-patient for greater than fourteen days were analyzed for reasons responsible. We reviewed 717 consecutive hip fractures. The average length of stay was 28 days. Forty-nine percent of patients stayed in hospital greater than 14 days. Reasons for prolonged stay included both medical and social reasons. Direct postoperative complications were rarely responsible for prolonged hospital stay. Hip fractures constitute a significant burden on acute trauma services. Further strategies are needed to address both medical and social reasons for prolonged stay in hospital following hip fracture, as is a prospective national hip fracture audit to quantify the burden on the Irish health service.

Incidence of hip fractures in Dublin's north inner city.

Hip fractures are an important cause of morbidity and mortality in the elderly and represent an increasing burden on health service providers. There is significant regional and international variation in the incidence rates of such injuries, depending on age, sex and ethnic variations in populations. To date, there are no reported incidence rates for hip fractures in Ireland. Over a five year period, 717 low energy hip fractures were treated in the orthopaedic trauma unit of the Mater Misericordiae hospital. For this population, the female to male ratio was 3.3:1 (549 females and 166 males), the gender specific incidences were 470 per 100,000 and 179 per 100,000 for females and males, respectively. The overall age standardized rate was 341 per 100,000. This study quantifies the burden of hip fracture on a local population. With this knowledge, health service providers should be able to allocate appropriate resources for these patients in terms of acute and step-down care facilities.

Incidence of hip fracture in the Republic of Ireland and future projections: a population-based study.

SUMMARY: There are no previously published data for hip fracture incidence rates in the Republic of Ireland. The rates of fracture for the total population aged 50 years and over were 407 and 140 per 100,000 for females and males, respectively. Assuming a stable incidence rate, the absolute number of hip fractures occurring on an annual basis is expected to increase by 100% by the year 2026. Health care providers should accommodate these increases into future strategies. INTRODUCTION: Hip fractures are an important cause of morbidity in the elderly and represent an increasing burden on health service providers. Significant regional and international variation in incidence rates of hip fracture exists. In order for health service providers to be able to commit adequate resources to the care of hip fracture patients, accurate estimates of hip fracture numbers are required now and for the future. To date, there have been no reported incidence rates for hip fracture in the Republic of Ireland. METHODS: We performed a search of the national hospital in-patient enquiry database for all hip fractures occurring in the Republic of Ireland between 2000 and 2004. Population data was obtained from the 2002 national census data. Population projections were made for the years 2016 and 2026 to allow determination of expected hip fracture numbers for those years. RESULTS: The rates of hip fracture in the Irish population aged 50 years and over were 407 and 140 per 100,000 for females and males, respectively. Annual hip fracture numbers are expected to increase by 100% by the year 2026, assuming a stable incidence rate. CONCLUSION: Health service providers should take into account the expected increase in hip fracture numbers when allocating resources for the care of these patients in the mid-term future.

Normal variants in the paediatric orthopaedic population.

Normal variations of lower limb development are a common source of parental concern and are commonly referred to paediatric orthopaedic clinics. To determine the proportion of children referred to a paediatric orthopaedic outpatients with potentially normal developmental variations, referral letters and case notes of children attending the paediatric orthopaedic clinic at our institution over three months were analysed and categorized according to the main reason for referral. The number with true orthopaedic pathology was documented. Variations of normal anatomy and physiology accounted for 53.1% of all new referrals seen at the clinic with intoeing and flexible flat feet being the commonest referrals in this category. The rate of true primary pathology was only 16.3%. Normal developmental variations form a significant proportion of all new referrals to paediatric orthopaedic clinics. These take time and resources to process. Strategies to minimise these referrals are needed.

Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds.

Novel ruthenium(II) organo-metallic compounds are active in ovarian cancer models [Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, et al. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer. Br J Cancer 2002;86(10):1652-7]. [(eta6-C6H5C6H5)Ru(en)Cl]+ (as a PF6 salt, where en=ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (approximately 10-fold lower than mean IC50) was noted in breast cancer and non-small cell lung cancer cell lines. In addition, IC50 in the A549 was 2 microM and RM175 (25 mg kg-1, days 1 and 5, i.p.) caused a significant (p=0.004) growth delay in a xenograft model. HC11 [(eta6-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 microM). HC11 (25 mg kg-1, days 1, 8 and 15, i.p.) was also active in vivo. Following RM175 25 mg kg-1, days 1 and 5, and 15 mg kg-1, days 1-5, HC11 25 and 40 mg kg-1, day 1, elevated alanine transaminase levels were detected, suggesting hepatotoxicity. No changes were observed in kidney or haematological parameters. In liver sections, multi-focal hepatic necrosis was seen, becoming confluent at high doses of HC11. In vitro studies confirmed that HC11 was more toxic than RM175 to fresh human hepatocytes and equitoxic to mithramycin. Liver toxicity may be related to the arene ligand and modification may reduce the potential for hepatic toxicity, while maintaining the anti-tumour activity seen.

Ethics committee reviews and mutual acceptance: a pilot study.

AIMS: To develop a human research ethics committee (HREC) mutual acceptance (MA) model, based on the National Health and Medical Research Council's guidelines. The MA model aims to facilitate aspects of multicentre research and decrease the time taken to finalise the HREC review process. METHODS: Four HREC (The Alfred Hospital, Austin Health, Peter MacCallum Cancer Centre and Melbourne Health) agreed to participate in a 13-month pilot project to evaluate the MA model. Evaluation included times from submission to approval and stakeholder surveys. RESULTS: Seventeen consecutive studies were submitted to the MA pilot project. Stakeholders agreed that the MA model was efficient and effective and that submission and review processes had improved, with a demonstrable reduction in the levels of duplication. There was a 27% improvement in approval times for multicentre studies. CONCLUSIONS: Our (MA) model resulted in clear improvements in HREC processes and timelines. Stakeholder acceptance was high. This model provides a framework for a broader program of MA.

Trust and confidence: towards mutual acceptance of ethics committee approval of multicentre studies.

AIMS: To compare issues raised by Human Research Ethics Committees (HREC) during the ethics review process and to determine the length of time taken to gain HREC approval for multicentre research studies. METHODS: Review and analysis of HREC documentation and correspondence for all multicentre research studies were conducted through three HREC under the auspices of Cancer Trials Australia, Melbourne, Victoria, Australia, between November 1997 and March 2001 to determine the variance of documentation, correspondence and recommendations across the three HREC and the time taken for study approval. RESULTS: Thirty-one projects were submitted to any two of the HREC (16 studies) or all three HREC (15 studies). The median time for study approval at an individual HREC was 75 days, but it was 111 days for approval at all participating sites. There were 554 clarifications or comments made by the reviewing HREC, the majority of which had no significant bearing on the ethical or scientific calibre of the study. There was only one study in which a significant protocol change was requested by a HREC. CONCLUSIONS: Multicentre study approvals are delayed when submitted to multiple HREC. The three HREC raised similar issues without substantive differences in their recommendations. A process for the mutual acceptance of HREC recommendations could facilitate multicentre research.