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1.  Pharmacovigilance in Hospice/Palliative Care: Net Effect of Haloperidol for Delirium 
Journal of Palliative Medicine  2013;16(11):1335-1341.
Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients.
A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced.
Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days.
Overall, 1 in 3 participants gained net clinical benefit at 10 days.
PMCID: PMC3822394  PMID: 24138282
2.  The Longitudinal Pattern of Response When Morphine Is Used To Treat Chronic Refractory Dyspnea 
Journal of Palliative Medicine  2013;16(8):881-886.
While evidence supports using sustained release morphine for chronic refractory breathlessness, little is known about the longitudinal pattern of breathlessness intensity as people achieve symptomatic benefit. The aim of this study is to describe this pattern.
This secondary analysis used breathlessness intensity scores (100 mm visual analogue scale (VAS)) from a prospective, dose increment study of once daily (morning) sustained release morphine for chronic refractory breathlessness. Participants who achieved <10% improvement over their own baseline at one week (10 mg) were titrated to 20 mg and if no response, another week later to 30 mg for one week. Time was standardized at the first day of the week in which participants responded generating twice daily data one week either side of symptomatic benefit. Analysis used random effect mixed modeling.
Of the 83 participants, 17/52 responders required >10 mg: 13 participants (20 mg) and 4 (30 mg), contributing 634 VAS observations. In the week leading to a response, average VAS scores worsened by 0.3 mm/day (p=0.16); the average improvement in the first 24 hours of response was 10.9 mm (7.0 to 14.7; p<0.0001), with continued improvement of 2.2 mm/day (p<0.001) for six more days.
When treating chronic refractory breathlessness with once daily sustained release morphine, titrate to effect, since inadequate dose may generate no response; and following an initial response, further dose increases should not occur for at least one week. Whether further benefit would be derived beyond day six on the dose to which people respond, and what net effect a further dose increase would have are questions yet to be answered.
PMCID: PMC3718325  PMID: 23746231
3.  Safety and treatment volumes achieved following new developments of the magnetic resonance-guided focused ultrasound system in the treatment of uterine fibroids: a cohort study 
This research investigates whether modifications to the magnetic resonance-guided focused ultrasound ablation of uterine fibroid (MRgFUS) system used resulted in improved treatment volumes of uterine fibroids, while maintaining safety.
This study is a prospective cohort analysis of 34 women undergoing the ExAblate 2100 MRgFUS treatment for their uterine fibroids.
The percentage of non-perfused volume (NPV) achieved with the ExAblate 2100 system was 54.92% compared with 50.49 % with the ExAblate 2000 system over the preceding year (p = 0.543). The ExAblate 2100 system resulted in a greater NPV in hyper-intense fibroids compared with the ExAblate 200 system (43.20% versus 36.33%, p = 0.005). There have been no recorded hospital admissions, no skins burns, and no reported major adverse events since the introduction of this new system.
Overall, the new system has thus far shown an encouraging safety record and an improvement in non-perfused volumes achieved, especially in hyper-intense fibroids.
PMCID: PMC4265952  PMID: 25512863
Uterine fibroids; Magnetic resonance-guided focused ultrasound; Leiomyoma
4.  Factors associated with initiation and exclusive breastfeeding at hospital discharge: late preterm compared to 37 week gestation mother and infant cohort 
To investigate and examine the factors associated with initiation of, and exclusive breastfeeding at hospital discharge of, late preterm (34 0/7 - 36 6/7 weeks) compared to 37 week gestation (37 0/7 - 37 6/7 week) mother and baby pairs.
A retrospective population-based cohort study using a Perinatal National Minimum Data Set and clinical medical records review, at the Royal Hobart Hospital, Tasmania, Australia in 2006.
Late preterm and 37 week gestation infants had low rates of initiation of breastfeeding within one hour of birth, 31 (21.1%) and 61 (41.5%) respectively. After multiple regression analysis, late preterm infants were less likely to initiate breastfeeding within one hour of birth (OR 0.3 95% CI 0.1, 0.7 p = 0.009) and were less likely to be discharged exclusively breastfeeding from hospital (OR 0.4 95% CI 0.1, 1.0 p = 0.04) compared to 37 week gestation infants.
A late preterm birth is predictive of breastfeeding failure, with late preterm infants at greater risk of not initiating breastfeeding and/or exclusively breastfeeding at hospital discharge, compared with those infants born at 37 weeks gestation. Stratifying breastfeeding outcomes by gestational age groups may help to identify those sub-populations at greatest risk of premature cessation of breastfeeding.
PMCID: PMC3546019  PMID: 23181740
Exclusive breastfeeding; Initiation; Late preterm; Infant
5.  Ankle-Brachial Index determination and peripheral arterial disease diagnosis by an oscillometric blood pressure device in primary care: validation and diagnostic accuracy study 
BMJ Open  2012;2(5):e001689.
To determine the level of agreement between a ‘conventional’ Ankle-Brachial Index (ABI) measurement (using Doppler and mercury sphygmomanometer taken by a research nurse) and a ‘pragmatic’ ABI measure (using an oscillometric device taken by a practice nurse) in primary care. To ascertain the utility of a pragmatic ABI measure for the diagnosis of peripheral arterial disease (PAD) in primary care.
Cross-sectional validation and diagnostic accuracy study. Descriptive analyses were used to investigate the agreement between the two procedures using the Bland and Altman method to determine whether the correlation between ABI readings varied systematically. Diagnostic accuracy was assessed via sensitivity, specificity, accuracy, likelihood ratios, positive and negative predictive values, with ABI readings dichotomised and Receiver Operating Curve analysis using both univariable and multivariable logistic regression.
Primary care in metropolitan and rural Victoria, Australia between October 2009 and November 2010.
250 persons with cardiovascular disease (CVD) or at high risk (three or more risk factors) of CVD.
Despite a strong association between the two method's measurements of ABI there was poor agreement with 95% of readings within ±0.4 of the 0.9 ABI cut point. The multivariable C statistic of diagnosis of PAD was 0.89. Other diagnostic measures were sensitivity 62%, specificity 92%, positive predictive value 67%, negative predictive value 90%, accuracy 85%, positive likelihood ratio 7.3 and the negative likelihood ratio 0.42.
Oscillometric ABI measures by primary care nurses on a population with a 22% prevalence of PAD lacked sufficient agreement with conventional measures to be recommended for routine diagnosis of PAD. This pragmatic method may however be used as a screening tool high-risk and overt CVD patients in primary care as it can reliably exclude the condition.
PMCID: PMC3488728  PMID: 23100446
Primary Care; Vascular Medicine; Public Health
6.  A prospective study of the impact of musculoskeletal pain and radiographic osteoarthritis on health related quality of life in community dwelling older people 
Pain and radiographic changes are common in persons with osteoarthritis, but their relative contributions to quality of life are unknown.
Prospective cohort study of 1098 men and women aged 50–80 years, randomly selected from the electoral roll. Participants were interviewed at baseline and approximately 2.6 and five years later. Participants self-reported prior diagnosis of arthritis and presence of joint pain. Joint space narrowing (JSN) and osteophytes at the hip and knee were assessed by X-ray. Quality of life (QoL) was assessed using the Assessment of QoL (AQoL) instrument. Data was analysed using linear regression and mixed modelling.
The median AQoL score at baseline was 7.0, indicating very good QoL. Prevalence of pain ranged from 38-62%. Over five years of observation, pain in the neck, shoulders, back, hips, hands, knees and feet were all independently and negatively associated with QoL, in a dose–response relationship. Diagnosed osteoarthritis at all sites was associated with poorer QoL but after adjustment for pain, this only remained significant at the back. Radiographic OA was not associated with QoL. While AQoL scores declined over five years, there was no evidence of an interaction between pain and time.
Pain is common in older adults, is stable over time, and the strongest musculoskeletal correlate of QoL. It also mediates the association between diagnosed OA and QoL. Since the same factors were associated with quality of life over time as at baseline, this suggests that quality of life tracks over a five year period.
PMCID: PMC3489889  PMID: 22954354
Quality of life; Ostearthritis; Knee; Osteoarthritis; Radiographic
7.  Decision aids for respite service choices by carers of people with dementia: development and pilot RCT 
Decision aids are often used to assist individuals confronted with a diagnosis of a serious illness to make decisions about treatment options. However, they are rarely utilised to help those with chronic or age related conditions to make decisions about care services. Decision aids should also be useful for carers of people with decreased decisional capacity. These carers' choices must balance health outcomes for themselves and for salient others with relational and value-based concerns, while relying on information from health professionals. This paper reports on a study that both developed and pilot tested a decision aid aimed at assisting carers to make evaluative judgements of community services, particularly respite care.
A mixed method sequential study, involving qualitative development and a pilot randomised controlled trial, was conducted in Tasmania, Australia. We undertook 13 semi-structured interviews and three focus groups to inform the development of the decision aid. For the randomised control trial we randomly assigned 31 carers of people with dementia to either receive the service decision aid at the start or end of the study. The primary outcome was measured by comparing the difference in carer burden between the two groups three months after the intervention group received the decision aid. Pilot data was collected from carers using interviewer-administered questionnaires at the commencement of the project, two weeks and 12 weeks later.
The qualitative data strongly suggest that the intervention provides carers with needed decision support. Most carers felt that the decision aid was useful. The trial data demonstrated that, using the mean change between baseline and three month follow-up, the intervention group had less increase in burden, a decrease in decisional conflict and increased knowledge compared to control group participants.
While these results must be interpreted with caution due to the small sample size, all intervention results trend in a direction that is beneficial for carers and their decisional ability. Mixed method data suggest the decision aid provides decisional support that carers do not otherwise receive. Decision aids may prove useful in a community health services context.
Trial registration number
PMCID: PMC3315425  PMID: 22429384
Decisional conflict; Decision aid; Dementia; Carer; Community services; Randomised-control trial; Qualitative
8.  Bone marrow lesions predict site-specific cartilage defect development and volume loss: a prospective study in older adults 
Arthritis Research & Therapy  2010;12(6):R222.
Recent evidence suggests that bone marrow lesions (BMLs) play a pivotal role in knee osteoarthritis (OA). The aims of this study were to determine: 1) whether baseline BML presence and/or severity predict site-specific cartilage defect progression and cartilage volume loss; and 2) whether baseline cartilage defects predict site-specific BML progression.
A total of 405 subjects (mean age 63 years, range 52 to 79) were measured at baseline and approximately 2.7 years later. Magnetic resonance imaging (MRI) of the right knee was performed to measure knee cartilage volume, cartilage defects (0 to 4), and BMLs (0 to 3) at the medial tibial (MT), medial femoral (MF), lateral tibial (LT), and lateral femoral (LF) sites. Logistic regression and generalized estimating equations were used to examine the relationship between BMLs and cartilage defects and cartilage volume loss.
At all four sites, baseline BML presence predicted defect progression (odds ratio (OR) 2.4 to 6.4, all P < 0.05), and cartilage volume loss (-0.9 to -2.9% difference per annum, all P < 0.05) at the same site. In multivariable analysis, there was a significant relationship between BML severity and defect progression at all four sites (OR 1.8 to 3.2, all P < 0.05) and BML severity and cartilage volume loss at the MF, LT, and LF sites (β -22.1 to -42.0, all P < 0.05). Additionally, baseline defect severity predicted BML progression at the MT and LF sites (OR 3.3 to 3.7, all P < 0.01). Lastly, there was a greater increase in cartilage volume loss at the MT and LT sites when both larger defects and BMLs were present at baseline (all P < 0.05).
Baseline BMLs predicted site-specific defect progression and cartilage volume loss in a dose-response manner suggesting BMLs may have a local effect on cartilage homeostasis. Baseline defects predicted site-specific BML progression, which may represent increased bone loading adjacent to defects. These results suggest BMLs and defects are interconnected and play key roles in knee cartilage volume loss; thus, both should be considered targets for intervention.
PMCID: PMC3046535  PMID: 21190554
9.  Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults 
Arthritis Research & Therapy  2010;12(6):R223.
There are conflicting data on the natural history and clinical significance of bone marrow lesions (BMLs). The aims of this study were to describe the natural history of MRI-detected BMLs at the knee using a quantitative measure and examine the association of BMLs with pain, function and stiffness scores, and total knee replacement (TKR) surgery.
A total of 395 older males and females were randomly selected from the general population (mean age 63 years, range 52 to 79) and measured at baseline and approximately 2.7 years later. BMLs were determined using T2-weighted fat saturation MRI by measuring the maximum area of the lesion. Reproducibility was excellent (intraclass correlation coefficient (ICC): 0.97). Pain, function, and stiffness were assessed by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores. X-ray was used to assess radiographic osteoarthritis (ROA) at baseline.
At baseline, 43% (n = 168/395) had a BML. Of these 25% decreased in size and 24% increased. Of the remaining sample (n = 227), 7% developed a new BML. In a multivariable model, a change in BML size was associated with a change in pain and function scores (β = 1.13 to 2.55 per 1 SD increase, all P < 0.05), only in those participants without ROA. Lastly, baseline BML severity predicted TKR surgery (odds ratio (OR) 2.10/unit, P = 0.019).
In a population based sample, BMLs (assessed by measuring maximal area) were not static, with similar proportions both worsening and improving. A change in BML size was associated with changes in pain in those without established ROA. This finding suggests that fluctuating knee pain may be attributable to BMLs in those participants with early stage disease. Baseline BMLs also predicted TKR surgery. These findings suggest therapeutic interventions aimed at altering the natural history of BMLs should be considered.
PMCID: PMC3046536  PMID: 21190555
10.  The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study 
The associations between leptin, interleukin (IL)-6, and hip radiographic osteoarthritis (OA) have not been reported, and their roles in obesity-related hip OA are unclear. The aim of this study was to describe the associations between leptin, IL-6, and hip radiographic osteoarthritis (ROA) in older adults.
A cross-sectional sample of 193 randomly selected subjects (mean age, 63 years; range, 52 to 78 years; 48% female subjects) were studied. Hip ROA, including joint-space narrowing (JSN) and osteophytes, was determined by anteroposterior radiograph. Serum levels of leptin and interleukin (IL)-6 were measured with radioimmunoassay. Fat mass was measured with dual-energy x-ray absorptiometry (DXA). Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated.
In multivariable analysis, hip JSN was associated with serum levels of leptin in the whole sample (β = 0.046 per μg/L, P = 0.024 for superior; β = 0.068 per μg/L, P = 0.004 for axial compartment) and IL-6 only in females (β = 0.241 per pg/ml, P = 0.002 for superior; β = 0.239 per pg/ml, P = 0.001 for axial compartment). The positive associations between body-composition measures (BMI, WHR, percentage total fat mass, and percentage trunk fat mass) and hip JSN in women became nonsignificant after adjustment for leptin but not for IL-6. No significant associations were found between leptin, IL-6, and the presence or severity of osteophytes.
This study suggests that metabolic and inflammatory mechanisms may play a role in the etiology of hip OA and that the associations between body composition and hip JSN are mediated by leptin, particularly in women.
PMCID: PMC2911879  PMID: 20482813
11.  A randomized single blind crossover trial comparing leather and commercial wrist splints for treating chronic wrist pain in adults 
To compare the effectiveness of a custom-made leather wrist splint (LS) with a commercially available fabric splint (FS) in adults with chronic wrist pain.
Participants (N = 25, mean age = 54) were randomly assigned to treatment order in a 2-phase crossover trial. Splints were worn for 2 weeks, separated by a one-week washout period. Outcomes were assessed at baseline and after each splint phase using the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), the Canadian Occupational Performance Measure (COPM) and Jamar dynamometer by an observer blinded to treatment allocation.
Both styles of wrist splint significantly reduced pain (effect size LS 0.79, FS 0.43), improved hand function and increased grip strength compared to baseline (all p < 0.05) with no increase in wrist stiffness. There was a consistent trend for the LS to be superior to the FS but this was statistically significant only for patient perceived occupational performance (p = 0.008) and satisfaction (p = 0.015). Lastly, 72% of patients preferred the custom-made leather splint compared to the commercially available splint.
Leather wrist splints were superior to a commercially available fabric splint for the short-term relief of pain and dysfunction.
PMCID: PMC2770479  PMID: 19843345
12.  Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease 
Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13–q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (P=0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the ITGA2 gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR=1.67 (1.07–2.6), P=0.0009) and rs1126643 (OR=1.52 (1.01–2.28), P=0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by in vivo and in vitro studies, supports a role for ITGA2 in tumour development.
PMCID: PMC2986161  PMID: 18830231
genetic; susceptibility; prostate; cancer; risk

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