Tim Badgery-Parker

Quality of life and other patient-reported outcomes following exenteration for pelvic malignancy

Pelvic exenteration is highly radical surgery offering the only potential cure for locally advanced pelvic cancer. This study compared quality of life and other relevant patient‐reported outcomes over 12 months for patients who did and those who did not undergo pelvic exenteration.

Characterisation of a novel, selective radioligand. [125I]Lys5, Tyr(I2)7,MeLeu9,Nle10]neurokinin A-(4-10), for the tachykinin NK2 receptor in rat fundus

The tyrosyl derivative of the tachykinin NK2 selective agonist [Lys5,MeLeu9,Nle10]NKA-(4-10) was iodinated and the product [125I][Lys5,Tyr(I2)2,MeLeu9,Nle10]NKA-(4-10) purified using reverse phase HPLC. The binding characteristics of this novel radioligand were investigated in homogenates of rat gastric fundus. Binding was saturable, reversible and to a single population of high affinity sites of KD 1.3 +/- 0.2 nM (n = 4). Specific binding of [125I][Lys5,Tyr(I2)7,MeLeu9,Nle10]NKA-(4-10) was inhibited by neuropeptide gamma SR 48968 > or = neurokinin A (NKA) > or = [Lys5,MeLeu9,Nle10]NKA-(4-10) > [Lys5,Tyr7,MeLeu9,Nle10] NKA-(4-10) > neuropeptide K > [Lys5,Tyr(I2)7,MeLeu9,Nle10]NKA-(4-10) > MDL 29,913 > [127I]- Bolton-Hunter-NKA > neurokinin B > substance P (SP) >> MEN 10207 > [Sar9,Met(O2)11]SP >> senktide, indicating binding to NK2 receptors. NKA, [Lys5,MeLeu9,Nle10]NKA-(4-10) and [Lys5,Tyr(I2)7,MeLeu9,Nle10]NKA-(4-10) contracted the isolated fundus strip, with pD2 values 7.9, 7.7 and 7.4, respectively. This novel, highly selective radioligand should prove useful in characterisation studies in peripheral tissues.

Tachykinin receptors in rabbit airways — characterization by functional, autoradiographic and binding studies

1 In many species, both NK1 and NK2 tachykinin receptors appear to be important in mediating the contraction of airway smooth muscle. We have examined the distribution and characterization of receptors for tachykinins in rabbit airways using functional length tension studies, autoradiography and radioligand binding studies. 2 Contractile responses to tachykinins were elicited in four different areas of the respiratory tree — trachea, and three progressively more distal areas of the right bronchus. The NK2 receptor‐preferring agonists, neurokinin A (NKA), neuropeptide gamma (NPγ) and the NK2‐selective [Lys5 MeLeu9, Nle10]‐NKA(4–10) [NKA (4–10) analogue] produced similar contraction in all four areas. Substance P (SP) and the NK1‐selective [Sar9,Met(O2)11]‐SP (Sar‐SP) exhibited a marked location‐dependence in the magnitude of contraction, producing minimal contraction in the trachea and more proximal bronchi with contractions becoming progressively larger in the more distal airways. Senktide (which is selective for the NK3 receptor) produced negligible contraction in all areas. 3 The NK2‐selective antagonist, MDL29,913, was a weak antagonist of NKA and NKA(4–10) analogue. At a concentration of 2 μm, it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4–10) analogue, but it had no effect on responses to Sar‐SP. The non peptide NK, receptor antagonist, CP‐96,345, was also unexpectedly weak in this preparation. The pD2 value for Sar‐SP was decreased 27 fold by CP‐96,345 at a concentration of 1 μm, without alteration in the maximum response. 4 Autoradiographic binding sites to [125I]‐NKA were sparse over smooth muscle in proximal airway preparations and markedly increased in density in the more distal airways. There was negligible binding over vascular smooth muscle and epithelium. 5 Radioligand binding studies revealed binding to [125I]‐NKA which was 82% specific. The order of potency for inhibition of [125I]‐NKA binding was SP >= Sar‐SP > NKA = NPγ>CP‐96,345 > NKA (4–10) analogue > NKB ⋙ MEN 10207 (the NK2 subtype selective antagonist) > MDL 29,913 > senktide. This profile indicates binding predominantly to NK1 receptors. 6 These results suggest that there are at least two types of tachykinin receptors in rabbit airways, a population of NK1 receptors, the density of which is greatest in the periphery and, in addition, NK2 receptors which are uniformly distributed throughout the airways. These receptors have unusual characteristics in that the NK1 antagonist, CP‐96,345 and the NK2 antagonist, MDL 29,913 respectively exhibited only weak potency.

Trends in use of neonatal CPAP: a population-based study.

BackgroundContinuous positive airway pressure (CPAP) is used widely to provide respiratory support for neonates, and is often the first treatment choice in tertiary centres. Recent trials have demonstrated that CPAP reduces need for intubation and ventilation for infants born at 25-28 weeks gestation, and at > 32weeks, in non-tertiary hospitals, CPAP reduces need for transfer to NICU. The aim of this study was to examine recent population trends in the use of neonatal continuous positive airway pressure.MethodsWe undertook a population-based cohort study of all 696,816 liveborn neonates ≥24 weeks gestation in New South Wales (NSW) Australia, 2001-2008. Data were obtained from linked birth and hospitalizations records, including neonatal transfers. The primary outcome was CPAP without mechanical ventilation (via endotracheal intubation) between birth and discharge from the hospital system. Analyses were stratified by age ≤32 and > 32 weeks gestation.ResultsNeonates receiving any ventilatory support increased from 1,480 (17.9/1000) in 2001 to 2,486 (26.9/1000) in 2008, including 461 (5.6/1000) to 1,465 (15.8/1000) neonates who received CPAP alone. There was a concurrent decrease in mechanical ventilation use from 12.3 to 11.0/1000. The increase in CPAP use was greater among neonates > 32 weeks (from 3.2 to 11.8/1000) compared with neonates ≤32 weeks (from 18.1 to 32.7/1000). The proportion of CPAP > 32 weeks initiated in non-tertiary hospitals increased from 6% to 30%.ConclusionsThe use of neonatal CPAP is increasing, especially > 32 weeks gestation and among non-tertiary hospitals. Recommendations are required regarding which infants should be considered for CPAP, resources necessary for a unit to offer CPAP and monitoring of longer term outcomes.

Receptor binding profile of neuropeptide γ and its fragments: Comparison with the nonmammalian peptides carassin and ranakinin at three mammalian tachykinin receptors

The tachykinin binding site preferences of neuropeptide gamma (NP gamma), its C-terminal fragments AcNP gamma(3-21), AcNP gamma(5-21), AcNP gamma(7-21), and AcNP gamma(9-21), other mammalian tachykinins, and the nonmammalian tachykinins ranakinin and carassin were examined in membrane binding competition studies. [125I]-Bolton-Hunter [Sar9,Met(O2)11]SP (BHSarSP), [125I]-neurokinin A (INKA) and [125I]-Bolton-Hunter scyliorhinin II (BHScyII) were used to investigate NK-1, NK-2, and NK-3 sites, in rat submandibular gland, gastric fundus, and brain, respectively. Elongation of the neurokinin A molecule does not appear to influence binding to rat tachykinin NK-1 and NK-2 binding sites. Ranakinin has affinity for the NK-1 and NK-2 site similar to that of substance P and neurokinin A, respectively, but has low affinity for the NK-3 site. Despite its structural similarities to neuropeptide gamma, carassin has only moderate affinity for rat tachykinin binding sites. Possession of an acidic residue at position 4 appears critical for binding to rat NK-2 sites.

Patterns and outcomes of preterm hospital admissions during pregnancy in NSW, 2001-2008

Objective: To assess the frequency and outcomes of preterm hospital admissions during pregnancy, with a focus on transfers to higher levels of care.

Survival of Australian lung cancer patients and the impact of distance from and attendance at a thoracic specialist centre: a data linkage study

Background Lung cancer patients have better survival when treated in thoracic surgical (specialist) centres. Aims To determine whether outcome of non-small cell lung cancer (NSCLC) patients is poorer with increasing distance to the nearest accessible specialist hospital (NASH). Methods We linked cancer registry, hospital and death records of 23 871 NSCLC patients; 3240 localised, 2435 regional and 3540 distant stage patients hospitalised within 12 months of diagnosis were analysed. Distance from patients’ residences to the NASH was measured using geographical coordinates. Cox proportional hazards models examined predictors of NSCLC death. Results Having a resection of the cancer, which admission to a specialist hospital made more likely, substantially reduced hazard of NSCLC death. Distance influenced hazard of death through both these variables; a patient was less likely to be admitted to a specialist hospital than a general hospital and less likely to have a resection the further they lived from the NASH. However, patients who lived distant from the NASH and were admitted to a specialist hospital were more likely to have a resection and less likely to die from NSCLC than patients admitted to a specialist hospital and living closer to the NASH. These patterns varied little with lung cancer stage. Conclusions NSCLC outcome is best when patients are treated in a specialist hospital. Greater distance to the NASH can affect its outcome by reducing the likelihood of being treated in a specialist hospital. Research is needed into patient and health service barriers to referral of NSCLC patients for specialist care.

Multifetal pregnancies: preterm admissions and outcomes.

OBJECTIVE To describe the rates of antenatal hospital admission during twin or higher order multifetal pregnancies, and the admission outcomes as discharge undelivered, transfer to higher care, or spontaneous or elective delivery. METHODS Cohort study using linked birth and hospital data. The cohort comprised women who gave birth to twins or higher order multiple infants of≥24 weeks gestation in 2001-2008 and who were admitted to hospital in weeks 20-36 of the pregnancy. RESULTS In 63.4% of 10 779 twin pregnancies and 99.5% of 197 triplet and quadruplet pregnancies, the woman was admitted to hospital at least once in weeks 20-36 of the pregnancy, for a total 10 985 admissions. Almost half the admissions (46.3%) ended in discharge without delivery, 10.7% in transfer to higher care, 21.1% in spontaneous labour and birth, and 21.8% in elective delivery (induction or prelabour Caesarean section). The reason for admission was preterm labour in 34.2% of admissions. CONCLUSIONS Hospital admission during pregnancy is common for women with multifetal pregnancies, with many of these admissions resulting in preterm birth. This is the first study to report the rate of pregnancy admissions for women with multifetal pregnancies, and provides a baseline for future studies of hospital use in this population.

A novel, selective radioligand, [125I]-[Lys5, Tyr(I2)7, Meleu9, Nle10]-NKA(4–10), for the tachykinin NK-2 receptor

A new radioligand, [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10), based on the selective agonist [Lys5,MeLeu9,Nle10]-NKA(4-10) has been developed. Binding in rat fundus membranes was displaced by NP gamma > NKA > or = [Lys5,MeLeu9,Nle10]-NK(4-10) > neuropeptide K > [Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) > SP > [Sar9,Met(O2)11]-SP >> senktide, indicating binding to NK-2 receptors. Preliminary studies demonstrated high specific binding in membranes from rat urinary bladder, duodenum and colon. Specific binding in rat brain and lung was negligible, and binding in a range of guinea-pig tissues was no more than 35% specific. These data may indicate species differences in NK-2 receptors.

A methodological protocol for selecting and quantifying low-value prescribing practices in routinely collected data: an Australian case study

BackgroundGrowing imperatives for safety, quality and responsible resource allocation have prompted renewed efforts to identify and quantify harmful or wasteful (low-value) medical practices such as test ordering, procedures and prescribing. Quantifying these practices at a population level using routinely collected health data allows us to understand the scale of low-value medical practices, measure practice change following specific interventions and prioritise policy decisions. To date, almost all research examining health care through the low-value lens has focused on medical services (tests and procedures) rather than on prescribing. The protocol described herein outlines a program of research funded by Australia’s National Health and Medical Research Council to select and quantify low-value prescribing practices within Australian routinely collected health data.MethodsWe start by describing our process for identifying and cataloguing international low-value prescribing practices. We then outline our approach to translate these prescribing practices into indicators that can be applied to Australian routinely collected health data. Next, we detail methods of using Australian health data to quantify these prescribing practices (e.g. prevalence of low-value prescribing and related costs) and their downstream health consequences. We have approval from the necessary Australian state and commonwealth human research ethics and data access committees to undertake this work.DiscussionThe lack of systematic and transparent approaches to quantification of low-value practices in routinely collected data has been noted in recent reviews. Here, we present a methodology applied in the Australian context with the aim of demonstrating principles that can be applied across jurisdictions in order to harmonise international efforts to measure low-value prescribing. The outcomes of this research will be submitted to international peer-reviewed journals. Results will also be presented at national and international pharmacoepidemiology and health policy forums such that other jurisdictions have guidance to adapt this methodology.