Building a sustainable clinical academic workforce to meet the future healthcare needs of Australia and New Zealand: report from the first summit meeting.

The delivery of healthcare that meets the requirements for quality, safety and cost-effectiveness relies on a well-trained medical workforce, including clinical academics whose career includes a specific commitment to research, education and/or leadership. In 2011, the Medical Deans of Australia and New Zealand published a review on the clinical academic workforce and recommended the development of an integrated training pathway for clinical academics. A bi-national Summit on Clinical Academic Training was recently convened to bring together all relevant stakeholders to determine how best to do this. An important part understood the lessons learnt from the UK experience after 10 years since the introduction of an integrated training pathway. The outcome of the summit was to endorse strongly the recommendations of the medical deans. A steering committee has been established to identify further stakeholders, solicit more information from stakeholder organisations, convene a follow-up summit meeting in late 2015, recruit pilot host institutions and engage the government and future funders.

A prospective evaluation of an interdisciplinary nutrition-rehabilitation program for patients with advanced cancer.

BACKGROUND: Cancer can affect many dimensions of a patient's life, and in turn, it should be targeted using a multimodal approach. We tested the extent to which an interdisciplinary nutrition-rehabilitation program can improve the well-being of patients with advanced cancer. METHODS: Between January 10, 2007, and September 29, 2010, 188 patients with advanced cancer enrolled in the 10-12-week program. Body weight, physical function, symptom severity, fatigue dimensions, distress level, coping ability, and overall quality of life were assessed at the start and end of the program. RESULTS: Of the enrolled patients, 70% completed the program. Patients experienced strong improvements in the physical and activity dimensions of fatigue (effect sizes: 0.8-1.1). They also experienced moderate reductions in the severity of weakness, depression, nervousness, shortness of breath, and distress (effect sizes: 0.5-0.7), and moderate improvements in Six Minute Walk Test distance, maximal gait speed, coping ability, and quality of life (effect sizes: 0.5-0.7) Furthermore, 77% of patients either maintained or increased their body weight. CONCLUSIONS: Interdisciplinary nutrition-rehabilitation can be advantageous for patients with advanced cancer and should be considered an integrated part of standard palliative care.

Conflict of interest: will it ever end?

Despite the inclusion of investigator-industry pecuniary and non-pecuniary associations in published clinical trials, the benefit of such disclosures may be limited. Two recent pivotal phase III drug studies that raised conflict of interest issues are discussed. It is recommended that in the future, a firewall should be erected between industry and investigators.

Modeling electrokinetic flows with the discrete ion stochastic continuum overdamped solvent algorithm.

In this article we develop an algorithm for the efficient simulation of electrolytes in the presence of physical boundaries. In previous work the discrete ion stochastic continuum overdamped solvent (DISCOS) algorithm was derived for triply periodic domains, and was validated through ion-ion pair correlation functions and Debye-Hückel-Onsager theory for conductivity, including the Wien effect for strong electric fields. In extending this approach to include an accurate treatment of physical boundaries we must address several important issues. First, the modifications to the spreading and interpolation operators necessary to incorporate interactions of the ions with the boundary are described. Next we discuss the modifications to the electrostatic solver to handle the influence of charges near either a fixed potential or dielectric boundary. An additional short-ranged potential is also introduced to represent interaction of the ions with a solid wall. Finally, the dry diffusion term is modified to account for the reduced mobility of ions near a boundary, which introduces an additional stochastic drift correction. Several validation tests are presented confirming the correct equilibrium distribution of ions in a channel. Additionally, the methodology is demonstrated using electro-osmosis and induced-charge electro-osmosis, with comparison made to theory and other numerical methods. Notably, the DISCOS approach achieves greater accuracy than a continuum electrostatic simulation method. We also examine the effect of under-resolving hydrodynamic effects using a "dry diffusion" approach, and find that considerable computational speedup can be achieved with a negligible impact on accuracy.

A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic.

A recombinant (r)65-kD protein from Mycobacterium leprae, at levels far in excess of those present in whole mycobacteria, was unable to induce arthritis. Even when combined with a synthetic adjuvant, CP20961, to mimic the peptidoglycan adjuvant component of the mycobacterial cell wall, the r65-kD protein failed to induce arthritis. Pretreatment with as little as 1 microgram r65-kD protein protected rats against arthritis induced by M. tuberculosis, but this r65-kD protein was markedly less able to protect against arthritis induced by the synthetic adjuvant, CP20961, or type II collagen. The r65-kD protein appears, therefore, to produce an antigen-specific protection against arthritis induced by bacterial cell walls containing the 65-kD protein. Such protection can be overcome, however, by arthritogenic T lymphocytes, suggesting that protection occurs by preventing clonal proliferation of autoreactive T lymphocytes that are induced by the adjuvant properties of mycobacterial cell walls. How the r65-kD protein abrogates this particular adjuvant activity, and the nature of the arthritogenic self antigen(s), remain to be elucidated.

Effect of magnesium deficiency on renal magnesium and calcium transport in the rat.

Recollection of micropuncture experiments were performed on acutely thyroparathyroidectomized rats rendered magnesium deficient by dietary deprivation. Urinary magnesium excretion fell from a control of 15 to 3% of the filtered load after magnesium restriction. The loop of Henle, presumably the thick ascending limb, was the major modulator for renal magnesium homeostasis. The transport capacity for magnesium, however, was less in deficient rats than control animals. Absolute magnesium reabsorption increased with acute infusions of magnesium chloride but was always less in magnesium-deficient rats than control rats for any given filtered load, which suggests either a defect of a resetting of the reabsorption mechanism. Recollection micropuncture demonstrated that this was a characteristic of the loop of Henle. Proximal magnesium reabsorption remained unchanged at 15% of the filtered load and was unaffected by magnesium deficiency or acute magnesium repletion. Distal tubular magnesium reabsorption was limited during depletion and increased to a similar extent in control and deficient rats with enhanced magnesium delivery. Calcium reabsorption was not altered in magnesium deficiency; however, elevations of extracellular magnesium resulted in a specific inhibition of calcium reabsorption within the loop of Henle. These data suggest that overall control of renal magnesium reabsorption occurs within the loop of Henle and that the proximal tubule reabsorbs a constant fraction of the filtered load despite variations in body magnesium status.

Adult height of preterm infants: a longitudinal cohort study.

BACKGROUND: Many infants born prematurely experience growth failure following delivery, with subsequent catch-up growth. Traditionally catch-up was thought to be complete in the first few years of life. Most studies have focused on groups of infants defined by birth weight, for example <1500 g, resulting in disproportionate numbers of small for gestational age infants. This study aimed to determine whether appropriate weight for gestation (AGA) preterm born children reach their expected adult height when compared with term controls. METHODOLOGY: This UK based prospective longitudinal cohort study recruited 204 preterm children born at a tertiary neonatal unit during 1994 and 50 matched controls. Growth parameters have been assessed annually until the completion of growth. RESULTS: There was no significant difference in the final height SD score (SDS) of children born at term (n=30) and those born prematurely and AGA (n=70) (0.45 term vs 0.22 preterm). Catch-up growth however, continued throughout the whole of childhood. When the difference between final height SDS and mid-parental height SDS were compared, there were again no significant differences (0.13 term vs 0.03 preterm). CONCLUSIONS: Those born prematurely with an AGA achieve a comparable adult height to children born at term, however, catch-up growth continues for much longer than traditionally thought.

Lithium versus antidepressants in the long-term treatment of unipolar affective disorder.

BACKGROUND: The main rationale for the use of lithium in the long-term treatment of unipolar affective disorder is its efficacy in treating bipolar affective disorder and resistant depression. However, there is considerable uncertainty about which pharmacological intervention is most effective in the long-term treatment of recurrent unipolar affective disorder. OBJECTIVES: To assess the effects of lithium versus antidepressants for the long-term treatment of recurrent affective disorder. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) on 2/9/2005. Reference lists of relevant papers and major textbooks of affective disorder were checked. Experts in the field and pharmaceutical companies were contacted regarding unpublished material. SELECTION CRITERIA: Randomised controlled trials comparing lithium against antidepressant medication for the long-term treatment of patients with a diagnosis of affective disorder. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: Eight trials involving 475 people were included. Two of the studies included a mixed group of participants with either bipolar or unipolar disorder. Relapse was defined as admission to hospital and when all kinds of relapses were considered (both depressive and manic), there was a statistically significant difference in favour of lithium (relative risk (RR) fixed effect 0.34, 95% CI 0.14 to 0.82). The results did not exclude the point of no effect, when the random-effects model was used (RR random effects 0.40, 95% CI 0.14 to 1.18). There were no other statistically significant differences between lithium and antidepressants according to all other outcomes considered. Manic or depressive relapse was defined as prescription of non-study medication for mood disorder, manic or depressive relapse (as defined by the study authors), quality of life, social functioning, occupational functioning, overall drop-out rate, drop-out rate due to side-effects, troublesome side-effects, mortality due to all causes and specifically suicides. AUTHORS' CONCLUSIONS: There was adequate efficacy evidence for lithium or antidepressants preventing relapse in unipolar affective disorder, however their relative efficacy was unknown. When considering lithium or antidepressant long-term therapy, patients and clinicians should take into account the patient's clinical history, the side-effects and the individual's likely adherence to the recommended treatment regime. Large-scale, long-term randomised trials in unselected groups of subjects with unipolar affective disorder are needed.

Development of a laboratory test for knicker tearing re-creation studies.

False sexual assault and rape claims result in wasted forensic and police resources and stigma for the alleged offender. In this work a laboratory method was developed to (i) recreate the ripping of knickers and (ii) measure the force required to rip the garments. The effect of laundering was considered as a means to mimic age of garment, and the effect of speed of ripping was used as a measure of forcible removal of garments. Whilst laundering resulted in visual damage to the thongs, it did not affect the mechanical properties. Faster test speeds resulted in higher measured forces and increased levels of damage. This may allow comment to be made regarding the level of force used during an attack.

Complementation Analysis of Metabolite-Resistant Mutations with Forced Heterokaryons of NEUROSPORA CRASSA.

The double mutant strain pyr-3 arg-12(s) is a prototroph because a common precursor of arginine and pyrimidine is supplied by the arginine pathway. Growth of this strain is inhibited by exogenous citrulline or arginine. Citrulline-resistant mutants of this strain were selected, and they resulted from modifier mutations at other loci. Forced heterokaryons were used to study complementation among these modifiers. Since the complementation test requires the scoring of non-growth as the positive result, there was concern that variations in nuclear ratios could give erroneous results. This possibility does not seem significant, since groups of mutants established by complementation correspond with groups established by physiological, enzymatic, and recombinational measurements.-The technique has revealed that the most frequently mutated loci are arg-1 and what is probably un-3. Arg-1 mutations affect the conversion of citrulline to argininosuccinate, while un-3 mutations reduce the citrulline uptake rate. Since most of these mutations are of the intracistronic complementing type, a complementation map was constructed for most of the affected loci. The high proportion of complementors in each map can be explained by assuming that partially functioning gene products are more likely to complement with each other than are those which are nonfunctional.

Evolutionary changes over the fifty-year history of a hybrid population of sunflowers (Helianthus).

Although there are many studies of the evolution and ecology of hybrid zones, few extend over long enough time periods to track evolutionary changes in the zones or assess the ultimate outcome of hybridization. Here we describe the current genetic and morphological composition of a hybrid sunflower population relative to its initial makeup 50 years ago. It appears that few genetically pure parental plants remain in the hybrid population and the average phenotype has shifted from an initial bias toward Helianthus bolanderi to a predominance of H. annuus-like plants. The similarity to H. annuus is more pronounced for morphology than for neutral genetic markers. In contrast to the shift in morphology that occurred primarily in the past 40 years, overall pollen viability increased to its current level during the first 10 to 15 years of hybridization, indicating the presence of strong fertility selection. Dramatic differences are seen in morphology, genetics, and pollen viability between the eastern and western halves of the population, thus confirming observations by previous authors and suggesting that selection pressures in the two halves differ. The trends seen in this hybrid population over the past 50 years suggest that H. bolanderi is undergoing genetic assimilation, and this trend may be representative of its fate throughout its range.

Main results of the losartan versus amlodipine (LOA) study on drug tolerability and psychological general well-being. LOA Study Group.

OBJECTIVE: To compare two losartan regimens (with and without hydrochlorothiazide) and amlodipine in treating mild-to-moderate hypertension regarding their blood-pressure-lowering effect, drug tolerability and quality of life. DESIGN: A 12-week, randomized, double-blind, parallel-group, multi-centre study. After 4 weeks of placebo, patients with a diastolic blood pressure (DBP) in the range 95-115 mmHg were allocated randomly to be administered 50 mg losartan (increased to 100 mg if the DBP was 90 mmHg or more after 6 weeks), 50 mg losartan (plus 12.5 mg hydrochlorothiazide under the above conditions), or 5 mg amlodipine (increased to 10 mg under the above condition). The tolerability of the treatment and the quality of life were evaluated by spontaneous reporting, active questioning and the Psychological General Well-Being (PGWB) index. STUDY POPULATION: In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men. RESULTS: Administration of 50 mg losartan (plus 12.5 hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure as well as or better than did 50 mg losartan (or 100 mg if necessary). The incidence of 'any discomfort' and 'swollen ankles' increased with amlodipine but not with losartan treatment. The opposite was found for 'dizziness upon standing'. The incidence of drug-related adverse events and the number of patients withdrawn from therapy were higher with amlodipine than they were with losartan treatment. The PGWB index at week 12 indicated that improvements from baseline had occurred in some domains for the losartan groups whereas it remained unchanged for the amlodipine group. CONCLUSION: Both losartan and amlodipine were effective in lowering the blood pressure and were tolerated well. Administration of 50 mg losartan (plus 12.5 mg hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure equally well or better than did 50 mg losartan (or 100 mg if necessary). Drug-related adverse effects and withdrawal from the study were more common for the amlodipine group. The clinical significance of the improvements in the PGWB index with losartan needs to be studied further.

Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially depending on length of fluoxetine administration, which could contribute in explaining the slow onset of antidepressant activity observed with selective serotonin reuptake inhibitors.

Antihypertensive effects of mibefradil in the treatment of mild-to-moderate systemic hypertension.

This report summarizes the results of 4 double-blind, placebo-controlled studies designed to determine the efficacy, tolerability, and dose-response characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of mild-to-moderate essential hypertension. Two of these studies were conducted in the general population of essential hypertensives, 1 in elderly patients, and 1 in patients on chronic hydrochlorothiazide treatment. A total of 1,116 patients were randomized to receive 1 of 7 doses of mibefradil (6.25-200 mg; n = 927), or placebo (n = 189). Each study demonstrated a significant linear dose response in the reduction of sitting diastolic (SDBP) and sitting systolic (SSBP) blood pressure. In all 4 trials, SDBP was significantly reduced with the recommended doses of 50 and 100 mg mibefradil (placebo-corrected treatment effects of -4.1 to -6.8 mm Hg and -8.8 to -11.1 mm Hg, respectively, for the 50- and 100-mg doses). A similar reduction in SSBP occurred in 3 of 4 studies at the 50-mg dose (-7.5 to -10.7 mm Hg) and in 4 of 4 studies at the 100-mg dose (-6.8 to -16.7 mm Hg). Lower doses did not reduce blood pressure significantly; doses > 100 mg had little additional effect and an increased incidence of adverse events. Overall, response and normalization rates were dose related and averaged 61% and 51%, respectively, for the 50-mg dose and 78% and 65%, respectively, for the 100-mg dose. The onset of the antihypertensive effect was gradual, with no first-dose effect; near maximal response was reached within 1-2 weeks. Trough/peak ratios ranged from 77-86% with the 50-mg dose and from 77-108% with the 100-mg dose, indicating a sustained effect over a 24-hour period. A slight decrease in heart rate was observed, ranging from -2.2 to -5.5 beats/min at the 50-mg dose and from -4.0 to -8.8 beats/min at the 100-mg dose. The efficacy and safety results were similar across all populations studied, including the elderly and hydrochlorothiazide-treated patients, indicating that no dose adjustment is needed for these populations. Thus, the results of these 4 placebo-controlled trials confirm that when taken at the recommended doses of 50 and 100 mg once daily, mibefradil is an effective, safe, and well-tolerated therapy for the treatment of mild-to-moderate hypertension.

Effects of tiaprofenic acid and other NSAIDs on proteoglycan metabolism in articular cartilage explants.

Using in vitro methods, we have determined the effects of four NSAIDs on the biosynthesis and turnover of proteoglycans in articular cartilage explants. Over the concentration ranges examined (5 X 10(-7) to 10(-5) mol/L for tiaprofenic acid, naproxen and indomethacin; 5 X 10(-5) to 10(-3) mol/L for aspirin), all the drugs examined, except tiaprofenic acid, reduced the rate of proteoglycan synthesis compared with control tissue. All of the compounds examined reduced the turnover rate of newly synthesised proteoglycans. The products of turnover of explants treated with the various NSAIDs did not appear to be significantly different from those produced by control tissue, as assessed by gel chromatography and electrophoresis. There were some indications, however, of quantitative differences in distribution on both these analytical systems. These results indicate that with the exception of tiaprofenic acid all the NSAIDs examined produced a general reduction in chondrocyte metabolic activity. Thus it seems unlikely that tiaprofenic acid would have a direct detrimental effect on articular cartilage during long term administration.

Suicide over 60: the San Diego study.

OBJECTIVES: To see if selected clinical factors characterize suicides over the age of 60 differently from younger suicides and to ascertain if those factors characterize female and male suicides over the age of 60 differently. DESIGN: A group of consecutive suicides aged 60-88 was compared with groups of consecutive suicides aged 31-59 and 16-30. The female suicides aged 60-88 were also compared with the male suicides in that age group. Data were gathered from a variety of informants using a structured interview format. SETTING: The sample was gathered in San Diego County, California, between November, 1981 and September 1982. PARTICIPANTS: The sample consisted of 204 consecutive suicides. These included 49 cases aged 60-88, 94 cases aged 31-59, and 61 cases aged 16-30. The older group consisted of 20 females and 29 males. MEASUREMENTS: Comparisons were made in demographic, diagnostic, and other clinical characteristics. RESULTS: There were no significant differences between female and male suicides over age 60 on any of the variables examined. Only minor differences were found among the groups in patterns of mental disorders diagnosed. Older suicides were significantly more likely to be married or, if not married, widowed than either of the two younger groups. They were also significantly more likely to be stressed by medical illness. They were significantly less likely to have financial problems as stressors. They were significantly less likely to have talked about suicide or made prior suicide attempts than either of the two younger groups. CONCLUSIONS: Patterns of certain characteristics of suicides are very similar regardless of age. However, specific age-related differences occur that need to be considered when assessing suicide risk. Older suicides may be harder for clinicians to predict and, therefore, prevent.

Aicardi syndrome: more than meets the eye.

An eight-month-old girl with infantile spasms and apparent blindness had electroencephalographic findings compatible with Aicardi syndrome. In addition to optic nerve hypoplasia, there were multiple congenital retinal malformations in the right eye, including chorioretinal lacunae, anomalous retinal vessels, posterior scleral ectasia, and a peripheral fibrous ridge. Magnetic resonance imaging demonstrated agenesis of the corpus callosum, absence of the septum pellucidum, optic nerve and chiasmal hypoplasia, pachygyria, cortical heterotopias, colpocephaly, and hypoplasia of the cerebellar vermis. This patient illustrates the broad spectrum of cerebroretinal malformations now known to characterize Aicardi syndrome.

Designing a Medicare prescription drug benefit: issues, obstacles, and opportunities.

We review the policy concerns underlying some of the most contentious issues that must be resolved prior to the enactment of a Medicare drug benefit. We consider critical issues both in benefit design-targeted versus universal eligibility, benefit subsidies, and benefit comprehensiveness--and in benefit administration, focusing especially on issues involving the administration of the drug benefit in traditional Medicare. Despite the apparent contentiousness of the drug benefit debate, alternative proposals may not be so far apart on these issues.