Medicinal Cannabis (MedCan 3): a randomised, multicentre, double-blind, placebo-controlled trial to assess THC/CBD (1:20) to relieve symptom burden in patients with cancer-a study protocol for a randomised controlled trial.

BACKGROUND: Distressing symptoms are common in advanced cancer. Medicinal cannabinoids are commonly prescribed for a variety of symptoms. There is little evidence to support their use for most indications in palliative care. This study aims to assess a 1:20 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom distress in patients with advanced cancer undergoing palliative care. METHODS AND DESIGN: One hundred and fifty participants will be recruited across multiple sites in Queensland, Australia. A teletrial model will facilitate the recruitment of patients outside of major metropolitan areas. The study is a pragmatic, multicenter, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:20 THC/CBD medicinal cannabinoid preparation (10 mg THC:200 mg CBD/mL). It will compare the efficacy and safety outcomes of a titrated dose range of 2.5 mg THC/50mgCBD to 30 mg THC/600 mg CBD per day against a placebo. There is a 2-week patient-determined titration phase, to reach a dose that achieves symptom relief or intolerable side effects, with a further 2 weeks of assessment on the final dose. The primary objective is to assess the effect of escalating doses of a 1:20 THC/CBD medicinal cannabinoid preparation against placebo on change in total symptom distress score, with secondary objectives including establishing a patient-determined effective dose, the effect on sleep quality and overall quality of life. Some patients will be enrolled in a sub-study which will more rigorously evaluate the effect on sleep. DISCUSSION: MedCan-3 is a high-quality, adequately powered, placebo-controlled trial which will help demonstrate the utility of a THC:CBD 1:20 oral medicinal cannabis product in reducing total symptom distress in this population. Secondary outcomes may lead to new hypotheses regarding medicinal cannabis' role in particular symptoms or in particular cancers. The sleep sub-study will test the feasibility of using actigraphy and the Insomnia Severity Index (ISI) in this cohort. This will be the first large-scale palliative care randomised clinical trial to utilise the teletrial model in Australia. If successful, this will have significant implications for trial access for rural and remote patients in Australia and internationally. TRIAL REGISTRATION: ANZCTR ACTRN12622000083796 . Protocol number 001/20. Registered on 21 January 2022. Recruitment started on 8 August 2022.

Cannabidiol oil or placebo in advanced cancer-disease progression and survival: a secondary analysis.

OBJECTIVES: Medical cannabinoids have become increasingly popular over the last decade. Preclinical trials suggest cannabinoids, for example, cannabidiol (CBD), may provide an anticancer effect; however, good-quality clinical information supporting this is lacking. We assessed the effect of CBD treatment on disease progression and survival in patients enrolled in a study of CBD versus placebo for symptom management in patients with advanced cancer (MEDCAN-1). METHODS: We reviewed the clinical records of all patients enrolled in the MEDCAN-1 Study (CBD vs placebo) at days 14, 28 and 56 of study follow-up, for evidence of disease progression. The proportion of participants with disease progression by treatment arm at each time point was compared, as was survival between both groups from study entry to the censor date (end of study period) and the effect of treatment arm and disease progression status on survival. RESULTS: Of the 135 patient records assessed, 128 were included in the final analysis. 36% (n=46) had progressive disease documented at day 28, rising to 49.2% (n=63) by day 56. No significant difference in disease progression was noted between the two groups at days 14 (p=0.33), 28 (p=0.67) or 56 (p=0.50). There was no difference in survival between both groups from study entry to censor date (p=0.38). Disease progression at day 14 was highly predictive of mortality (p<0.001). CONCLUSIONS: In this substudy analysis, treatment with CBD oil did not affect disease progression or survival over the course of 56 days in patients with advanced cancer.

Exploring potential anti-inflammatory effects of medicinal cannabis.

PURPOSE: Inflammation is thought to play a key role in malignant disease and may play a significant part in the expression of cancer-related symptoms. Cannabidiol (CBD) is a bioactive compound in cannabis and is reported to have significant anti-inflammatory properties. METHOD: Serial C-reactive protein (CRP) levels were measured in all participants recruited to a randomised controlled trial of CBD versus placebo in patients with symptoms related to advanced cancer. A panel of inflammatory cytokines was measured over time in a subset of these patients. RESULTS: There was no difference between the two arms in the trajectory of CRP or cytokine levels from baseline to day 28. CONCLUSION: We were unable to demonstrate an anti-inflammatory effect of CBD in cancer patients. TRIAL REGISTRATION: ANZCTR 26180001220257, registered 20/07/2018.

Drug dependence epidemiology in palliative care medicinal cannabis trials.

OBJECTIVES: Drug dependence is becoming increasingly common and meeting palliative care patients with substance use disorders is inevitable. However, data on substance use in these patients are lacking. This study aims to evaluate the prevalence of drug dependence in palliative care patients with advanced cancer and correlate with symptom distress and opioid use. METHODS: Palliative care patients with advanced cancer interested in participation in a medicinal cannabis trial were required to complete Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), Edmonton Symptom Assessment Scale (ESAS) and record of concomitant medications including baseline opioid use as part of the eligibility screen. RESULTS: Of the 182 participants, 167 (92%) reported lifetime alcohol and 132/182 (73%) lifetime tobacco use. No participant reached the threshold criteria for high risk of drug dependence with majority being low risk. There was no correlation between ASSIST score, ESAS and oral morphine equivalent. CONCLUSION: This study identified alcohol and tobacco as the main substances used in this group of patients and that most were of very low risk for drug dependence. This suggests routine drug screening for palliative care patient may not be justified, but the high possibility of questionnaire bias is acknowledged.

Human intravenous immunoglobulin use for hematological immune-mediated disease in dogs.

OBJECTIVE: To report on survival rates and risk factors in dogs with immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (ITP) treated with human IV immunoglobulin (hIVIG; Privigen). We hypothesized that hIVIG could be used as a salvage treatment to improve survival and reduce the requirement for ongoing blood transfusion therapy in IMHA and ITP patients. ANIMALS: 52 client-owned dogs with IMHA or ITP were included, comprising 31 females (28 spayed and 3 entire) and 21 males (19 castrated and 2 entire). Miniature Schnauzers were the most common breed (5), with a further 24 different breeds identified. PROCEDURES: A retrospective cohort study was conducted between January 2006 and January 2022 that assessed the survival rates, risk factors, and need for ongoing transfusion in dogs with IMHA and ITP treated with hIVIG compared with those not receiving hIVIG. RESULTS: Of 36 dogs that did not receive hIVIG, 29 (80%) survived and 7 (24%) died, and of 16 dogs administered hIVIG, 11 (69%) survived and 5 (31%) died (P = .56). No effect of PCV at admission or age on the risk of death was detected (OR, 1.00; 95% CI, 0.94 to 1.08; P = .89; and OR, 1.10; 95% CI, 0.85 to 1.47; P = .47, respectively). CLINICAL RELEVANCE: This was the largest study to date of dogs with hematological immune-mediated disease treated with hIVIG. There was no difference in survival rates for dogs that received hIVIG versus those treated with standard immunosuppression. The benefit of hIVIG as a salvage treatment appears limited.

Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD).

PURPOSE: To determine whether cannabidiol (CBD) oil can improve symptom distress in patients with advanced cancer receiving palliative care. METHODS: Participants were adults with advanced cancer and symptom distress (Edmonton Symptom Assessment Scale [ESAS] total score of ≥ 10/90) who received titrated CBD oil 100 mg/mL, 0.5 mL once daily to 2 mL three times a day, or matched placebo for 28 days. The primary outcome was ESAS total symptom distress score (TSDS) at day 14. Response was defined as a decrease in TSDS by ≥ 6 at day 14. Secondary outcomes were ESAS TSDS over time, individual symptom scores, patient-determined effective dose, opioid use, Global Impression of Change, depression, anxiety, quality of life, and adverse events. RESULTS: Of the 144 patients randomly assigned, the planned sample size of 58 participants on CBD and 63 on placebo reached the primary analysis point (day 14). The unadjusted change in TSDS from baseline to day 14 was -6.2 (standard deviation, 14.5) for placebo and -3.0 (standard deviation, 15.2) for CBD with no significant difference between arms (P = .24). Similarly, there was no detected difference in proportion of responders (placebo: 37 of 63 [58.7%], CBD: 26 of 58 [44.8%], P = .13). All components of ESAS improved (fell) over time with no difference between arms. The median dose of participant-selected CBD was 400 mg per day with no correlation with opioid dose. There was no detectable effect of CBD on quality of life, depression, or anxiety. Adverse events did not differ significantly between arms apart from dyspnea that was more common with CBD. Most participants reported feeling better or much better at days 14 (53% CBD and 65% placebo) and 28 (70% CBD and 64% placebo). CONCLUSION: CBD oil did not add value to the reduction in symptom distress provided by specialist palliative care alone.

Survival Analysis of Training Methodologies and Other Risk Factors for Musculoskeletal Injury in 2-Year-Old Thoroughbred Racehorses in Queensland, Australia.

Musculoskeletal injuries remain a global problem for the Thoroughbred racing industry and there is conflicting evidence regarding the effect of age on the incidence of injuries. The ideal time to commence race training is strongly debated, with limited supporting literature. There is also conflicting evidence regarding the effect of high-speed exercise on musculoskeletal injuries. There is a strong interest in developing training and management strategies to reduce the frequency of injuries. The types of musculoskeletal injuries vary between 2-year-old and older horses, with dorsal metacarpal disease the most common injury in 2-year-old horses. It is likely that risk factors for injury in 2-year-old horses are different than those for older horses. It is also likely that the risk factors may vary between types of injury. This study aimed to determine the risk factors for musculoskeletal injuries and dorsal metacarpal disease. We report the findings of a large scale, prospective observational study of 2-year-old horses in Queensland, Australia. Data were collected weekly for 56-weeks, from 26 trainers, involving 535 2-year-old Thoroughbred racehorses, 1, 258 training preparations and 7, 512-weeks of exercise data. A causal approach was used to develop our statistical models, to build on the existing literature surrounding injury risk, by incorporating the previously established causal links into our analyses. Where previous data were not available, industry experts were consulted. Survival analyses were performed using Cox proportional hazards or Weibull regression models. Analysis of musculoskeletal injuries overall revealed the hazard was reduced with increased exposure to high-speed exercise [Hazard ratio (HR) 0.89, 95% Confidence Interval (CI) 0.84, 0.94, p < 0.001], increased number of training preparations (HR 0.58, 95% CI 0.50, 0.67, p < 0.001), increased rest before the training preparation (HR 0.89, 95% CI 0.83, 0.96, p = 0.003) and increased dam parity (HR 0.86, 95% CI 0.77, 0.97, p = 0.01). The hazard of injury was increased with increasing age that training commenced (HR 1.13, 95% CI 1.06, 1.19, p < 0.001). Analyses were then repeated with the outcome of interest dorsal metacarpal disease. Factors that were protective against dorsal metacarpal disease and musculoskeletal injuries overall included: increased total cumulative distance (HR 0.89, 95% CI 0.82, 0.97, p = 0.001) and total cumulative days exercised as a gallop (HR 0.96, 95% CI 0.92, 0.99, p = 0.03), the number of the training preparations (HR 0.43, 95% CI 0.30, 0.61, p < 0.001). The age that training commenced was harmful for both dorsal metacarpal disease (HR 1.17, 95% CI 1.07, 1.28, p < 0.001 and overall musculoskeletal injuries.). The use of non-ridden training modalities was protective for dorsal metacarpal disease (HR 0.89, 95% CI 0.81, 0.97, p = 0.008), but not musculoskeletal injuries overall. The male sex increased the hazard of DMD compared to females (HR 2.58, 95% CI 1.20, 5.56, p = 0.02), but not MSI overall. In summary, the hazard of musculoskeletal injury is greatest for 2-year-old horses that are born from uniparous mares, commence training at a later age, are in their first training preparation, have undertaken little high-speed exercise or had limited rest before their training preparation. The hazard of dorsal metacarpal disease is greatest for 2-year-old horses that are males, commence training at a later age, are in their first training preparation, have undertaken little high-speed exercise or had limited use of non-ridden training modalities. Close monitoring of these high-risk horses during their training program could substantially reduce the impact of MSI. Furthermore, an understanding of how training methodologies affect the hazard of MSI facilitates modification of training programs to mitigate the risk impact of injury. The strengths of this study include a large sample size, a well-defined study protocol and direct trainer interviews. The main limitation is the inherent susceptibility to survival bias.

The risk of recurrent small-for-gestational-age infants at term is dependent on the number of previously affected births.

BACKGROUND: Small-for-gestational-age infants are at a substantially increased risk of perinatal complications, but the risk of recurrent small-for-gestational-age is not well known, particularly because there are many demographic and obstetrical factors that interact and modify this risk. We investigated the relationship between previous small-for-gestational-age births and the risk of recurrence at term in a large Australian cohort. OBJECTIVE: We aimed to identify key demographic and obstetrical variables that influence the risk of recurrence of a small-for-gestational-age infant at term. The primary outcome measure was the odds of recurrence of small-for-gestational-age in subsequent pregnancies up to a maximum of 4 consecutive term births. STUDY DESIGN: This was a retrospective analysis of women who had more than 1 consecutive nonanomalous, singleton, term live births between July 1997 and September 2018 at the Mater Mother's Hospital in Brisbane, Australia. Women with multiple pregnancy, preterm birth, or major congenital malformations were excluded. Small-for-gestational-age was defined as birthweight at the <10th centile. We calculated the odds of recurrence depending on the number of previous small-for-gestational-age infants and if only the preceding infant was small-for-gestational-age. The study population was dichotomized into small-for-gestational-age and non-small-for-gestational-age for each consecutive pregnancy. Univariate analyses compared baseline demographic and obstetrical characteristics followed by logistic regression modeling to determine the odds of recurrence in the second, third, and fourth pregnancies. RESULTS: The final study comprised 24,819 women. The proportion of women who had a small-for-gestational-age infant in their first pregnancy was 9.4%, whereas the proportion of women who had a small-for-gestational-age infant in their second, third, and fourth pregnancies after the birth of a previous small-for-gestational-age infant were 20.5% (479 of 2338), 24.6% (63 of 256), and 30.4% (14 of 46), respectively. Regardless of parity, the odds of recurrence increased if the preceding infant was small-for-gestational-age. The odds of recurrence increased markedly if there was more than 1 previous small-for-gestational-age infant. In women with 3 previous small-for-gestational-age infants, the adjusted odds of another small-for-gestational-age infant were 66.00 (95% confidence interval, 11.35-383.76). Maternal age, body mass index, ethnicity, and smoking were significant risk factors for recurrent small-for-gestational-age. However, maternal diabetes mellitus or hypertension, either in a previous or current pregnancy, did not influence the risk of recurrence. CONCLUSION: The risk of recurrence in a subsequent pregnancy increased if there was a previous small-for-gestational-age birth. Women with consecutive small-for-gestational-age infants were at the highest risk of recurrence. Our results highlight that women with a previous small-for-gestational-age infant are at a substantial risk of another small infant and need to be counseled and monitored appropriately.

A Prospective Study of Training Methods for Two-Year-Old Thoroughbred Racehorses in Queensland, Australia, and Analysis of the Differences in Training Methods between Trainers of Varying Stable Sizes.

Worldwide, musculoskeletal injuries remain a major problem for the Thoroughbred racing industry. There is a strong interest in developing training and management strategies to reduce the impact of musculoskeletal injuries, however, progress has been limited by studies reporting conflicting findings, and a limited understanding of the role of different training methods in preventing injury. There is little data on patterns of rest periods and exercise data and how these vary between trainers. This prospective study of two-year-old racehorses was conducted in Queensland, Australia and involved weekly personal structured interviews with 26 trainers over 56 weeks. Detailed daily exercise data for 535 horses providing 1258 training preparations and 7512 weeks at risk were collected. Trainers were categorised into three groups by the mean number of two-year-old horses that they had in work each week over the study duration: (1) Small stables with five or less, (2) Medium stables with 6 to 15 and (3) Large stables with greater than 15 horses in training. Differences between trainers with small, medium and large stable sizes were evaluated using linear regression, Kruskal-Wallis equality-of-populations rank test if linear models were mis-specified or Chi-squared tests for categorical variables. Significant differences were observed between trainers, with horses from larger stables accumulating a greater high-speed exercise volume (p < 0.001), attaining training milestones more frequently (p = 0.01) and taking less time to reach their training milestones (p = 0.001). This study provides detailed data to which training practices from other locations can be compared. Presenting actual training data rather than trainers' estimation of a typical program provides a more accurate assessment of training practices. Understanding how training practices vary between regions improves comparability of studies investigating risk factors and is an important step towards reducing the impact of musculoskeletal injuries.

The Risk Factors for Musculoskeletal Injuries in Thoroughbred Racehorses in Queensland, Australia: How These Vary for Two-Year-Old and Older Horses and with Type of Injury.

Musculoskeletal injuries (MSI) continue to affect Thoroughbred racehorses internationally. There is a strong interest in developing training and management strategies to reduce their impact, however, studies of risk factors report inconsistent findings. Furthermore, many injuries and fatalities occur during training rather than during racing, yet most studies report racing data only. By combining racing and training data a larger exposure to risk factors and a larger number of musculoskeletal injuries are captured and the true effect of risk factors may be more accurately represented. Furthermore, modifications to reduce the impact of MSI are more readily implemented at the training level. Our study aimed to: (1) determine the risk factors for musculoskeletal injuries and whether these are different for two-year-old and older horses and (2) determine whether risk factors vary with type of injury. This was performed by repeating analyses by age category and injury type. Data from 202 cases and 202 matched controls were collected through weekly interviews with trainers and analysed using conditional logistic regression. Increasing dam parity significantly reduced the odds of injury in horses of all age groups because of the effect in two-year-old horses (odds ratio (OR) 0.08; 95% confidence interval (CI) 0.02, 0.36; p < 0.001). Increasing total preparation length is associated with higher odds of injury in horses of all ages (OR 5.56; 95% CI 1.59, 19.46; p = 0.01), but particularly in two-year-old horses (OR 8.05; 95% CI 1.92, 33.76; p = 0.004). Increasing number of days exercised at a slow pace decreased the odds of injury in horses of all ages (OR 0.09; 95% CI 0.03, 0.28; p < 0.001). The distance travelled at three-quarter pace and above (faster than 13 m/s; 15 s/furlong; 800 m/min; 48 km/h) and the total distance travelled at a gallop (faster than 15 m/s; 13 s/furlong; 900 m/min; 55 km/h) in the past four weeks significantly affected the odds of injury. There was a non-linear association between high-speed exercise and injury whereby the odds of injury initially increased and subsequently decreased as accumulated high-speed exercise distance increased. None of the racing career and performance indices affected the odds of injury. We identified horses in this population that have particularly high odds of injury. Two-year-old horses from primiparous mares are at increased odds of injury, particularly dorsal metacarpal disease. Two-year-old horses that have had a total preparation length of between 10 and 14 weeks also have increased odds of injury. Horses of all ages that travelled a total distance of 2.4-3.8 km (12-19 furlongs) at a gallop in the last four weeks and horses three years and older that travelled 3.0-4.8 km (15-24 furlongs) at three-quarter pace and above also have increased odds of injury. We recommend that these horses should be monitored closely for impending signs of injury. Increasing the number of days worked at a slow pace may be more effective for preventing injury, if horses are perceived at a higher risk, than resting the horse altogether. Early identification of horses at increased risk and appropriate intervention could substantially reduce the impact of musculoskeletal injuries in Thoroughbred racehorses.

Appraising the Welfare of Thoroughbred Racehorses in Training in Queensland, Australia: The Incidence, Risk Factors and Outcomes for Horses after Retirement from Racing.

There is international public concern regarding retirement of racehorses, including the reason for retirement and the outcome for horses after racing. However, there are currently no prospective studies investigating these factors. A recent independent inquiry in Queensland, Australia, highlighted that the true outcomes for horses after retirement from racing are largely unknown. Furthermore, there are currently no measures to monitor the outcome for racehorses and their welfare once they have left the care of the trainer. This study investigated these gaps in knowledge through a weekly survey conducted over a 13-month period. We aimed to evaluate: (1) the incidence of retirement, (2) the reasons and risk factors for retirement and (3) the medium-term (greater than 6 months) outcomes for horses after retirement. Data were collected through personal structured weekly interviews with participating trainers and analysed using negative binomial and logistic regression. There was a low incidence of retirements, namely 0.4% of horses in training per week. The season and training track did not affect the incidence of retirement. Musculoskeletal injuries were the most common reason for retirement (40/110 horses, 36%). Involuntary retirements accounted for 56/100 (51%) of retirements, whereby musculoskeletal injuries, respiratory or cardiac conditions and behavioural problems prevented the horse from racing The odds of voluntary retirement, whereby the horse was retired due to racing form or impending injury, increased with each additional race start (OR 1.05; p = 0.01) and start/year of racing (OR 1.21; p = 0.03) but decreased with increasing percentage of first, second and third places (OR 0.94; p < 0.001). Medium-term follow-up (median 14 months, IQR 11, 18, range 8-21) revealed that most horses (108/110; 98%) were repurposed after retirement, almost half as performance horses (50/110; 46%). Horses that voluntarily retired had 2.28 times the odds of being repurposed as performance horses than those retired involuntarily (p = 0.03). Whether retirement was voluntary or involuntary did not influence whether horses were used for breeding or pleasure. The primary limitation of this study is that our results reflect retirement in racehorses in South East Queensland, Australia, and may not be globally applicable. Furthermore, we were unable to monitor the long-term outcome and welfare of horses in their new careers. It is vital that the industry is focused on understanding the risks for voluntary rather than involuntary retirement and optimising the long-term repurposing of horses. There is a need for traceability and accountability for these horses to ensure that their welfare is maintained in their new careers.

Appraising the Welfare of Thoroughbred Racehorses in Training in Queensland, Australia: The Incidence and Type of Musculoskeletal Injuries Vary between Two-Year-Old and Older Thoroughbred Racehorses.

Musculoskeletal injuries (MSI) remain a concerning cause of racehorse morbidity and mortality with important ethical and welfare consequences. Previous research examining risk factors for MSI report inconsistent findings. Age is thought to affect MSI risk, but, to date, there have been no prospective studies comparing MSI in two-year-old versus older horses. This study aimed to: (1) determine the incidence of MSI for two-year-old and older horses, and whether this was affected by training track, season, or rainfall, and (2) determine the types of MSI affecting two-year-old and older horses, and whether horses trialled or raced after injury. A prospective survey was conducted with data collected through personal structured weekly interviews with participating trainers over a 13-month period. Data were analysed using Poisson regression. The incidence of MSI in the current study was low (0.6%). The incidence of MSI in two-year-old horses was higher than older horses (p < 0.001). Types of MSI varied between two-year-old and older horses (p < 0.001) and affected whether horses subsequently trailed or raced from 11 to 23 months after injury (p < 0.001). A larger proportion of two-year-old horses had dorsal metacarpal disease and traumatic lacerations. A smaller proportion of two-year-old horses had suspensory ligament desmitis, superficial digital flexor tendonitis, proximal sesamoid bone fractures, and fetlock joint injuries than older horses. Training track and rainfall did not affect MSI. The season affected MSI in two-year-old horses (p < 0.001) but not older horses. The major limitation was that trainers in this study were metropolitan (city) and our findings may not be generalisable to racehorses in regional (country) areas. Another significant limitation was the assumption that MSI was the reason for failure to trial or race after injury. In conclusion, the incidence of MSI was low in the current study and the types and the risk factors for MSI are different for two-year-old and older horses.

Genotypic diversity, circulation patterns and co-detections among rhinoviruses in Queensland, 2001.

PURPOSE: Rhinoviruses (RVs) occur more frequently than other viruses and more often in people displaying symptoms than in those without. We sought to estimate the spectrum of RV diversity, RV species seasonality and to analyse RV involvement in respiratory virus co-detections. METHODOLOGY: A convenience collection of 1179 airway sample extracts from patients with suspected respiratory infections, collected during 2001, was subjected to comprehensive molecular testing. RESULTS: RVs were the most common virus detected. We were able to genotype ~90 % of RV detections, identifying 70 distinct RVs, spanning all three species. RV-Bs were under-represented. We found RV species co-circulated at times, although one species usually dominated. Each species displayed a bimodal distribution. CONCLUSION: Notably, RVs and influenza A viruses (IFAV) seldom co-occurred, supporting their roles as primary pathogens of the airway among acutely ill infants. Whether RV circulation has a moderating or controlling effect on the IFAV season or is controlled by it cannot be determined from these data. Despite the frequent perception that RVs commonly co-occur with another virus, our findings indicated this was not always the case. Nearly 80 % of RV detections occurred alone. Understanding more about population-level interference between viruses may allow us to harness aspects of it to generate a non-specific antiviral intervention that mimics a putative protective effect. For routine respiratory virus screening to best serve the patient, RV testing should be a principal component of any acute respiratory illness testing algorithm throughout the year.

Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo-controlled, randomised clinical trial of efficacy and safety of 1:1 delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

BACKGROUND: Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids but little high-quality evidence to guide clinicians. This study aims to define the role of a 1:1 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. METHODS AND DESIGN: One hundred fifty participants will be recruited from five sites within the Queensland Palliative Care Research Group (QPCRG) and randomly assigned to an active treatment or placebo group. This study is a pragmatic multicentre, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:1 THC/CBD cannabinoid preparation. It will compare efficacy and safety outcomes of a titrated dose (10 mg/10 mg/mL oral solution formulation, dose range 2.5 mg/2.5 mg-30 mg/30 mg/day) against placebo. There is a 2-week patient-determined titration phase, using escalating doses of 1:1 THC/CBD or placebo, to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. The primary objective is to assess the effect of escalating doses of a 1:1 THC/CBD cannabinoid preparation against placebo on change in total symptom score, with secondary objectives including establishing a patient-determined effective dose, the change in total physical and emotional sores, global impression of change, anxiety and depression, opioid use, quality of life and adverse effects. DISCUSSION: This will be the first placebo-controlled clinical trial to rigorously evaluate the efficacy, safety and acceptability of 1:1 THC/CBD for symptom relief in advanced cancer patients. This study will allow the medical community to have some evidence to present to patients wishing to access cannabis for their symptoms caused by advanced malignancy. TRIAL REGISTRATION: ACTRN, ACTRN12619000037101 . Registered on 14 January 2019. Trial Sponsor: Mater Misericordiae Limited (MML) and Mater Medical Research Institute Limited (MMRI)-Raymond Terrace, South Brisbane, Brisbane, QLD, Australia.

An Open-Label Pilot Study Testing the Feasibility of Assessing Total Symptom Burden in Trials of Cannabinoid Medications in Palliative Care.

Background: There is considerable interest in the use of cannabinoids for symptom control in palliative care, but there is little high-quality evidence to guide clinical practice. Objectives: Assess the feasibility of using global symptom burden measures to assess response to medicinal cannabis, to determine median tolerated doses of cannabidiol (CBD) and tetrahydrocannabinol (THC), and to document adverse events (AEs). Design: Prospective two-arm open-label pilot trial of escalating doses of CBD and THC oil. Setting/Subjects: Participants had advanced cancer and cancer-related symptoms in a palliative and supportive care service in an Australian cancer center. Measurements: The main outcome measures were the number of participants screened and randomized over the time frame, the number of participants completing days 14 and 28 and providing total symptom distress scores (TSDSs) (measured using the Edmonton Symptom Assessment Scale), and the change from baseline of the TSDS at day 14. Results: Of the 21 participants enrolled (CBD, n = 16; THC, n = 5), 18 (86%) completed the primary outcome measure at day 14 and 8 completed at day 28. The median maximum tolerated doses were CBD, 300 mg/day (range 100-600 mg); THC, 10 mg/day (range 5-30 mg). Nine of 21 patients (43%) met the definition of response (≥6 point reduction in TSDS). Drowsiness was the most common AE. Conclusions: Trials of medicinal cannabis in advanced cancer patients undergoing palliative care are feasible. The doses of THC and CBD used in this study were generally well tolerated and the outcome measure of total symptom distress is promising as a measure of overall symptom benefit. Trial registration: ACTRN12618001205224.

Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).

BACKGROUND: Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. METHODS AND DESIGN: This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. DISCUSSION: A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms. TRIAL REGISTRATION NUMBER: ALCTRN12618001220257 Registered 20/07/2018.

Prelabour myocardial deformation and cardiac output in fetuses that develop intrapartum compromise at term: a prospective observational study.

Objective: Redistribution of cardiac output is responsible for the "brain sparing" effect seen during periods of acute or chronic fetal stress. We investigated the relationship between prelabour cardiac function in fetuses that subsequently developed intrapartum fetal compromise (IFC). Methods: A blinded, prospective, observational, cohort study, at Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent ultrasound every 2 weeks from 36 weeks until delivery. Fetal cardiac output was assessed by conventional Doppler ultrasound and myocardial deformation was measured using velocity vector imaging. Results: Two hundred and seventy three women were included in the final analysis, of which 19% had an emergency operative delivery for intrapartum fetal compromise (IFC). Global left ventricular strain (-12.1%, interquartile ranges (IQR) - 10.3 to -14% versus 13%, IQR -11.3 to -14.2%, p = .01) and strain rate (-1.00, IQR 0.85-1.16 s-1 versus -1.11, IQR -1.00 to -1.21 s-1, p < .001) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not. Global longitudinal right ventricular strain rate was lower in fetuses that developed IFC (-1.04 ± 0.22 s-1 versus 1.13 ± 0.22 s-1, p < .001), whereas global right ventricular strain did not show any significance differences between the two groups. Additionally, left ventricular cardiac output was lower in fetuses that developed IFC or had a composite neonatal morbidity (560 ± 44 mL/min versus 617 ± 72 mL/min, p < .001) or (581 ± 44 mL/min versus 612 ± 72 mL/min, p < .01), respectively. Conclusion: Lower global left ventricular strain and strain rate and cardiac output are associated with IFC and poorer condition of the newborn. Assessment of fetal cardiac function may be useful for risk stratification for intrapartum fetal compromise in apparently "low risk" term pregnancies.

Assessment of left ventricular function using the Myocardial Performance Index in term fetuses that develop intrapartum compromise.

OBJECTIVE: To investigate the relationship between the prelabour left ventricular Myocardial Performance Index (LVMPI) and intrapartum fetal compromise (IFC) in low-risk term pregnancies. METHODS: A blinded, prospective observational cohort study at the Mater Mother's Hospital, Brisbane, Australia. A cohort of 284 women with uncomplicated singleton pregnancies underwent fortnightly ultrasound from 36 weeks until delivery. The LVMPI was assessed by conventional Doppler ultrasound and correlated with intrapartum outcomes. The LVMPI was also correlated with other Doppler indices of fetal wellbeing. RESULTS: Two hundred and seventy-three women were included in the final analysis, the median LVMPI was higher in fetuses that required any emergency operative delivery for IFC (0.56, 0.52-0.60 versus 0.54, 0.50-0.58, p = .007). The left ventricular cardiac output (LVCO) and cerebroplacental ratio (CPR) were lower in fetuses that required any emergency operative delivery for IFC compared to those that did not (164 ± 19 ml/min/kg versus 181 ± 30 ml/min/kg, p < .001) (1.63 + 0.30 versus 1.90 + 0.50, p < .001), respectively. The LVMPI was inversely correlated with the CPR (r = -0.20, p < .01), MCA PI (r = -0.29, p < .01), and LVCO (r = -0.22, p < .01). CONCLUSIONS: Higher global LVMPI is associated with a higher risk for IFC and poorer condition of the newborn.

Reference centiles for the middle cerebral artery and umbilical artery pulsatility index and cerebro-placental ratio from a low-risk population - a Generalised Additive Model for Location, Shape and Scale (GAMLSS) approach.

OBJECTIVE: The primary aim of this study was to create reference ranges for the fetal Middle Cerebral artery Pulsatility Index (MCA PI), Umbilical Artery Pulsatility Index (UA PI) and the Cerebro-Placental Ratio (CPR) in a clearly defined low-risk cohort using the Generalised Additive Model for Location, Shape and Scale (GAMLSS) method. METHODS: Prospectively collected cross-sectional biometry and Doppler data from low-risk women attending the Mater Mother's Hospital, Maternal and Fetal Medicine Department in Brisbane, Australia between January 2010 and April 2017 were used to derive gestation specific centiles for the MCA PI, UA PI and CPR. All ultrasound scans were performed between 18 + 0 and 41 + 6 weeks gestation with recorded data for the MCA PI and/or UA PI. The GAMLSS method was used for the calculation of gestational age-adjusted centiles. Distributions and additive terms were assessed and the final model was chosen on the basis of the Global Deviance, Akaike information criterion (AIC) and Schwartz bayesian criterion (SBC), along with the results of the model and residual diagnostics as well as visual assessment of the centiles themselves. RESULTS: Over the study period 6013 women met the inclusion criteria. The MCA PI was recorded in 4473 fetuses, the UA PI in 6008 fetuses and the CPR was able to be calculated in 4464 cases. The centiles for the MCA PI used a fractional polynomial additive term and Box-Cox t (BCT) distribution. Centiles for the UA PI used a cubic spline additive term with BCT distribution and the CPR used a fractional polynomial additive term and a BCT distribution. CONCLUSION: We have created gestational centile reference ranges for the MCA PI, UA PI and CPR from a large low-risk cohort that supports their applicability and generalisability.

Identification of bacteria and fungi sampled from the conjunctival surface of normal horses in South-East Queensland, Australia.

OBJECTIVE: To identify bacteria and fungi found on the conjunctival surface of normal horse eyes; to investigate potential risk factors for these microflora; and to determine their susceptibility to common topical ophthalmic antimicrobials. ANIMALS STUDIED: A total of 95 client-owned horses were studied. PROCEDURES: Horses within sub-tropical Australia (South-East Queensland) were sampled once between April 2012 and March 2013. A conjunctival swab was taken from each eye and cultured for aerobic bacteria and fungi. Organisms were identified by colony morphology and phenotype. Antimicrobial disk diffusion susceptibility testing for commonly used antimicrobials was performed. RESULTS: Positive bacterial cultures were returned from 187/190 (98.4%) eyes from 94/95 (98.9%) horses. The most common species included Staphylococcus spp. (25.2% of total bacterial isolates), Bacillus cereus (17.4%), Bacillus spp. (14.1%), and Corynebacterium spp. (8.9%). Most bacterial isolates were susceptible to neomycin and fluoroquinolones. Positive fungal cultures were returned from 111/190 (58.4%) eyes from 73 (76.8%) horses. The most common species identified included: Penicillium spp. (16.7% of fungal isolates), Aspergillus spp. (15.4%), and Scopulariopsis spp. (10.3%). Most (≥90%) molds were susceptible to ketoconazole, voriconazole, itraconazole, and miconazole. Yeasts were most susceptible to ketoconazole. There was no significant effect of breed, age, sex, purpose, or housing of the horse or climatic conditions on bacterial or fungal culture status. CONCLUSIONS: Bacteria and fungi were commonly isolated from the eyes of healthy horses. The antibiotic and antifungal susceptibilities identified can be used as a guide for empirical therapy after cytology in the treatment of corneal ulceration in horses.