Reduced prevalence of pain and distress during 4 years of screening with QUICATOUCH in Australian oncology patients.

While psychosocial screening has been recommended in oncology for some time, widespread adoption in clinical practice has lagged. The QUICATOUCH program is one example of sustained clinic-level screening, assessment and referral. We examined whether this program was associated with reductions in pain or distress. Oncology outpatients completed a brief, computerised assessment using Distress and Pain Thermometers. We describe population levels of pain and distress and model pain and distress scores over 4 years of the program. 9,133 patients were screened on 26,385 occasions over 48 months (October 2007-September 2011). Pain over threshold (1/10) reduced over time, from 33% in the first 3 months to 16% in the final quarter of the evaluation. Distress over threshold (4/10) reduced from 28% to 10%. A reduction was also observed when restricted to patients screened for the first time. Our analysis demonstrated this effect was not explained by measured potential confounders (gender, age, treatment status) and was unlikely to be attributable to regression to the mean. Observational studies cannot prove causation. However, the significant reduction in pain and distress levels in the 48 months following commencement of QUICATOUCH is consistent with a beneficial effect of the program.

Mental health and other clinical correlates of euthanasia attitudes in an Australian outpatient cancer population.

A majority of patients with cancer have been reported to endorse euthanasia and physician assisted suicide (PAS) in general and a substantial proportion endorse these for themselves. However, the potential influence of mental health and other clinical variables on these decisions is not well understood. This study of 228 outpatients attending an oncology clinic in Newcastle, Australia used a cross-sectional design and logistic regression modelling to examine the relationship of demographic, disease status, mental health and quality of life variables to attitudes toward euthanasia and PAS. The majority reported support for euthanasia (79%, n=179), for PAS (69%, n=158) and personal support for euthanasia/PAS (68%, n=156). However, few reported having asked their doctor for euthanasia (2%, n=5) or PAS (2%, n=5). Three outcomes were modelled: support for euthanasia was associated with active religious belief (adjusted odds ratio (AOR) 0.21, 95% CI: 0.10-0.46); support for PAS was associated with active religious belief (AOR 0.35, 95% CI: 18-0.70) and recent pain (AOR 0.87, 95% CI: 0.0.76-0.99); and personal support for euthanasia/PAS was associated with active religious belief (AOR 0.26, 95% CI: 0.14-0.48). Depression, anxiety, recent suicidal ideation, and lifetime suicide attempt were not independently associated with any of the three outcomes modelled.

What people say about their general practitioners' treatment of anxiety and depression.

OBJECTIVE: To determine from self-report how often people with anxiety and depressive disorders consult GPs and what treatment they receive. DESIGN: The study was derived from the 1997 Australian National Survey of Mental Health and Wellbeing. A probability sample of adults was interviewed to determine how many had which mental disorders, how disabled they were by those disorders, and what treatment they had received. PARTICIPANTS: 10641 adults, a 78% response rate. MAIN OUTCOME MEASURES: Prevalence of anxiety and depressive disorders and related disability; frequency of consultations for a mental problem; treatment received. RESULTS: 13.6% of the population both met criteria for an anxiety or depressive disorder in the 12 months before the survey and, when they suffered from more than one disorder, nominated this as their principal complaint. They reported some disability in 7 of the previous 28 days, and consulted a GP or other health professional 1.4 times in that period. Over half did not seek a consultation for a mental health problem at any time during the year, many because they thought they had no need. CONCLUSION: Many people who could benefit from treatment for anxiety and depressive disorders are not being reached. If people were registered with a general practice it would be possible for GPs to take a proactive stance that could result in greater benefit to patients at a lower cost to the health system.

Lithium toxicity: an iatrogenic problem in susceptible individuals.

OBJECTIVE: Lithium toxicity, manifesting primarily as neurotoxicity, is a significant health problem and is primarily iatrogenic in nature. Despite 50 years of medical experience with lithium, factors contributing to the development of severe neurotoxicity remain poorly documented. We hypothesized that severe neurotoxicity represents the most clinically significant manifestation of lithium toxicity. We proposed that this occurs primarily in the context of chronic therapeutic administration ('chronic poisoning'), rather than in the context of an overdose. Furthermore we hypothesized that patients who developed chronic poisoning did so in the presence of identifiable factors which predictably impair lithium clearance. METHOD: A retrospective analysis of 97 cases of lithium poisoning, treated at a regional centre over a 13-year period was performed. Demographic data and factors considered likely to relate to the risk of developing lithium toxicity were recorded. Patients were classified according to mode of poisoning (acute, acute on chronic, or chronic) and according to severity of neurotoxicity (nil, mild, moderate, severe). The risk of developing severe neurotoxicity as a result of each mode of poisoning was assessed. The association between various risk factors and the development of chronic poisoning was assessed using a logistic regression model. RESULTS: Twenty-eight cases were rated as suffering severe neurotoxicity; in 26 this developed in the context of chronic poisoning and in two in the context of acute on chronic poisoning. All patients who developed severe neurotoxicity had at least one putative risk factor present, regardless of mode of poisoning. Length of stay was significantly longer for cases with severe neurotoxicity compared to those without severe neurotoxicity (12 vs. 2 days, P < 0.001). Peak serum lithium concentrations were significantly higher in cases with severe neurotoxicity compared to those without (2.3 vs. 1.6 mmol/L, P = 0.02). Patients presenting with chronic poisoning had a substantially higher risk of severe neurotoxicity than those presenting after an overdose of lithium (Odds Ratio [OR] 136, 95% CI 23-1300). A logistic regression model showed three factors contributed independently to the risk of chronic poisoning. These were: nephrogenic diabetes insipidus (adjusted OR 26.96, 95% CI 2.89-251.94), age over 50 years (adjusted OR 6.20, 95% CI 1.36-28.32) and thyroid dysfunction (adjusted OR 9.30, 95% CI 1.36-63.66). A fourth factor, baseline endogenous creatinine clearance below normal limits, was significant at the P = 0.05 level (adjusted OR 6.49, 95% CI 0.98-43.01). Hyperparathyroidism was noted in three cases of chronic poisoning suffering severe neurotoxicity. CONCLUSION: Severe lithium neurotoxicity occurs almost exclusively in the context of chronic therapeutic administration of lithium, and rarely results from acute ingestion of lithium, even in patients currently taking lithium. As such it is an iatrogenic illness, occurring in patients who have identifiable clinical risk factors: nephrogenic diabetes insipidus, older age, abnormal thyroid function and impaired renal function. Although administration of drugs which impair lithium clearance appeared to contribute minimally to chronic lithium poisoning in the absence of other factors, these drugs may well 'uncover' the predisposing risk factors and certainly should not be considered safe to use as a consequence of this study. The serious morbidity suffered by lithium toxic patients, and the cost to society due to long hospital stays, might be reduced by careful prescribing, vigilant monitoring and awareness of these factors, as they develop in otherwise stable patients. Review of existing therapeutic guidelines may be warranted.

Repetition of deliberate self-poisoning in an Australian hospital-treated population.

OBJECTIVES: To describe the hospital-treated prevalences for repeat deliberate self-poisoning (RDSP) and the demographic characteristics of the RDSP group, and to compare the RDSP and non-RDSP groups. DESIGN: Prospective longitudinal cohort study, with a one- to four-year follow-up. SETTING: The Hunter Area Toxicology Service (HATS), a regional toxicology treatment centre in New South Wales. SUBJECTS: 1238 consecutive DSP patients referred to hospital, 1992-1994, with follow-up through 1995. OUTCOME MEASURES: Deliberate self-poisoning (DSP) admissions within one year (RDSP-1), within six months (RDSP-6m), and within 28 days (RDSP-28d) of any other DSP admission by the same patient; length of stay; demographic characteristics; and drugs ingested. RESULTS: 175 patients (14.1%) repeated DSP during the study; 165 (13.3%) were classified as RDSP-1, giving a patient prevalence of hospitalisation in the range of 14.6 to 20.7 per 100,000 per year. Fifty-six RDSP-28d patients (33.9% of RDSP-1) accounted for 49.8% of the RDSP-1 admissions, and 123 RDSP-6m patients (74.5% of RDSP-1) accounted for 83.5% of RDSP-1 admissions. For RDSP-1, the male:female ratio was 1:1.9, with 35.7% unemployed, 29.1% pensioners and 15.8% married or in de facto relationships. RDSP-1 patients had a shorter length of stay (3 h), which was not clinically important. RDSP was more likely for the 25-34 years age group (odds ratio [OR], 2.24; 95% confidence interval [CI], 1.17-4.29) and the 35-44 years age group (OR, 2.12; 95% CI, 1.02-4.39) than the 10-18 years group, and more likely for women than men (OR, 1.69; 95% CI, 1.17-2.46). Being married/de facto reduced the risk for repetition (OR, 0.55; 95% CI, 0.31-0.96) compared with being single. Medications indicated for psychiatric illness were most commonly used for DSP. CONCLUSIONS: Many patients who repeat DSP do so after a very brief interval and account for a disproportionate number of hospitalisations. Availability of psychiatric medications for DSP patients is a possible area of intervention.

Features and toxicokinetics of clozapine in overdose.

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region. Another case from a different region is described. The cases were identified from the Hunter Area Toxicology Service Database and regional psychiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurred in the absence of prior exposure. No reversible electrocardiographic changes or biochemical abnormalities were demonstrated. Anticholinergic effects were minimal. All seven cases made full recovery. A high-pressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approximate retention times were norclozapine, 3.8 minutes; clozapine, 5 minutes; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite. Using the HPLC assay, serial clozapine and norclozapine plasma concentrations were measured in three of these cases of clozapine self-poisoning. Toxicokinetic modeling was conducted by simultaneous analysis of clozapine and norclozapine observations. A two-compartment model with a metabolite compartment attached to the central compartment was used. Clozapine metabolism to norclozapine was best described by linear elimination of norclozapine and nonlinear norclozapine formation. The Km (1918 +/- 2093 micrograms/l) relative to observed concentration (3396 +/- 962 micrograms/l) suggests that norclozapine formation was saturated at the time of the first observation.

Health care. A model for the management of self-poisoning.

OBJECTIVE: To describe the development and activity of a multidisciplinary service to manage self-poisoning. DESIGN: Descriptive, comparative study with prospective data collection. SETTING: Regional toxicology treatment centre in the Hunter area of New South Wales (NSW) with primary and secondary referral service to 385,000 people and tertiary referral service to a further 100,000. PATIENTS: All patients (1987-1995) with poisoning or envenomation presenting to the Hunter Area Toxicology Service (HATS). MAIN OUTCOME MEASURES: Average length of stay for HATS compared with national and NSW hospitals; mortality data for HATS compared with NSW. RESULTS: Average length of stay for HATS was 0.53-1.22 days shorter than for all Australian hospitals, potentially saving 518 bed-days, valued at $468,000 per year. Average length of stay was 0.94-3.39 days shorter than for all NSW hospitals, saving 1470 bed-days at $1.4 million per year. Inpatient mortality (0.2%; 95% confidence interval, 0.0-1.1) was not significantly different from NSW (0.5%; 95% CI, 0.2-0.8). Standardised mortality ratios showed no greater all-cause suicide mortality. CONCLUSIONS: In our centralised model for managing self-poisoning, all toxicology patients in an area health service are diverted to one hospital, where all patients with deliberate self-poisoning are admitted under the one multidisciplinary team, and all receive psychiatric assessment. This model has substantially reduced bed stay, with considerable savings to the Hunter Area Health Service manifested as an increase in beds available for other purposes.

Psychosocial sequelae of the 1989 Newcastle earthquake: II. Exposure and morbidity profiles during the first 2 years post-disaster.

BACKGROUND: A sample of 1089 Australian adults was selected for the longitudinal component of the Quake Impact Study, a 2-year, four-phase investigation of the psychosocial effects of the 1989 Newcastle earthquake. Of these, 845 (78%) completed a survey 6 months post-disaster as well as one or more of the three follow-up surveys. METHODS: The phase 1 survey was used to construct dimensional indices of self-reported exposure to threat the disruption and also to classify subjects by their membership of five 'at risk' groups (the injured; the displaced; owners of damaged small businesses; helpers in threat and non-threat situations). Psychological morbidity was assessed at each phase using the 12-item General Health Questionnaire (GHQ-12) and the Impact of Event Scale (IES). RESULTS: Psychological morbidity declined over time but tended to stabilize at about 12 months post-disaster for general morbidity (GHQ-12) and at about 18 months for trauma-related (IES) morbidity. Initial exposure to threat and/or disruption were significant predictors of psychological morbidity throughout the study and had superior predictive power to membership of the targeted 'at risk' groups. The degree of ongoing disruption and other life events since the earthquake were also significant predictors of morbidity. The injured reported the highest levels of distress, but there was a relative absence of morbidity among the helpers. CONCLUSIONS: Future disaster research should carefully assess the threat and disruption experiences of the survivors at the time of the event and monitor ongoing disruptions in the aftermath in order to target interventions more effectively.

Psychosocial sequelae of the 1989 Newcastle earthquake: III. Role of vulnerability factors in post-disaster morbidity.

BACKGROUND: This paper examines the contributions of dispositional and non-dispositional factors to post-disaster psychological morbidity. Data reported are from the 845 participants in the longitudinal component of the Quake Impact Study. METHODS: The phase 1 survey was used to construct dimensional indices of threat and disruption exposure. Subsequently, a range of dispositional characteristics were measured, including neuroticism, personal hopefulness and defence style. The main morbidity measures were the General Health Questionnaire (GHQ-12) and Impact of Event Scale (IES). RESULTS: Dispositional characteristics were the best predictors of psychological morbidity throughout the 2 years post-disaster, contributing substantially more to the variance in morbidity (12-39%) than did initial exposure (5-12%), but the extent of their contribution was greater for general (GHQ-12) than for post-traumatic (IES) morbidity. Among the non-dispositional factors, avoidance coping contributed equally to general and post-traumatic morbidity (pr = 0.24). Life events since the earthquake (pr = 0.18), poor social relationships (pr = -0.25) and ongoing earthquake-related disruptions (pr = 0.22) also contributed to general morbidity, while only the latter contributed significantly to post-traumatic morbidity (pr = 0.15). CONCLUSIONS: Medium-term post-earthquake morbidity appears to be a function of multiple factors whose contributions vary depending on the type of morbidity experienced and include trait vulnerability, the nature and degree of initial exposure, avoidance coping and the nature and severity of subsequent events.

Drug-induced delirium. Incidence, management and prevention.

Drugs may be the most frequent single cause of delirium, and very often they are a critical element in a multifactorial aetiology. While delirium may be precipitated by virtually any drug, certain classes of drugs are more commonly implicated. Effective management of drug-induced delirium involves recognition, cessation or dosage reduction of the causative drug(s), and initiation of reorientation strategies and supportive medical care. Specific "antidotes' are appropriate in only a few limited cases. Drug treatment aimed at sedation should be introduced for specific indications, such as aggression, risk of harm to self or others, hallucinations, patient distress, and where compliance with therapy or procedures is essential. Certain benzodiazepines (diazepam, lorazepam, midazolam) and/or haloperidol may be the most appropriate choices in these circumstances. Primary prevention requires the prescription of alternative lower risk medications and the minimisation of polypharmacy. Secondary prevention may be achieved through improved recognition of the condition.

Stress debriefing and patterns of recovery following a natural disaster.

Stress debriefing has been used extensively following traumatic events; however, there is little evidence of its effectiveness. This paper reports the effects of stress debriefing on the rate of recovery of 195 helpers (e.g., emergency service personnel and disaster workers) following an earthquake in Newcastle, Australia (62 debriefed helpers and 133 who were not debriefed). Post-trauma stress reactions (Impact of Event Scale) and general psychological morbidity (General Health Questionnaire: GHQ-12) were assessed on four occasions over the first 2 years postearthquake. There was no evidence of an improved rate of recovery among those helpers who were debriefed, even when level of exposure and helping-related stress were taken into account. More rigorous investigation of the effectiveness of stress debriefing and its role in posttrauma recovery is urgently required.

Psychosocial sequelae of the 1989 Newcastle earthquake: I. Community disaster experiences and psychological morbidity 6 months post-disaster.

A stratified random sample of 3007 Australian adults completed a screening questionnaire 6 months after the 1989 Newcastle earthquake. Information was obtained on initial earthquake experiences and reactions, use of specific services, social support, coping strategies and psychological morbidity. This questionnaire was the first phase of the Quake Impact Study, a longitudinal project investigating the psychosocial impact of the earthquake. Two weighted indices of exposure were developed: a threat index, which measured exposure to injury or the possibility of injury; and a disruption index, which measured experiences of property damage, displacement and other losses. Levels of exposure to threat and disruption events were significant predictors of morbidity on both the General Health Questionnaire and Impact of Event Scale, as were coping style and gender. Effects of exposure to threat and disruption were largely additive, with higher exposure being associated with greater use of support services, higher perceived stressfulness and more severe psychological morbidity. Use of avoidance as a coping strategy, female gender, lower social support and being older were also associated with higher post-disaster psychological distress. It was estimated that 14.8% of the population was exposed to high levels of threat or disruption, of whom approximately 25% experienced moderate to severe psychological distress as a direct result of the disaster. It was further estimated that 18.3% of those exposed to high levels of threat were at risk of developing post-traumatic stress disorder, representing approximately 2% of the city's adult population.

Patterns of service utilisation following the 1989 Newcastle earthquake: findings from phase 1 of the Quake Impact Study.

A screening questionnaire was distributed to 5,000 adult members of the community six months after the 1989 Newcastle earthquake, with a response rate of 63 per cent (n = 3,007). The mean age of respondents was 46.7 years and 58 per cent were female. Subjects' earthquake experiences were rated in terms of weighted indices of exposure to threat and disruption. Psychological morbidity was measured using the General Health Questionnaire and the Impact of Event Scale. Subjects were asked to indicate which of a range of general and disaster-related support services they had used in dealing with the stressful effects of the earthquake. It was estimated that 21.3 per cent of the adult population used general and/or disaster-related support services. Users of these services reported greater exposure to threat and/or disruption and had higher levels of psychological distress than nonusers. However, a high level of use of general services and reliance on medical services were related more to psychological morbidity than degree of exposure to earthquake-related events. Overall, the Newcastle community's needs for assistance in the aftermath of the earthquake were effectively absorbed by the existing support services and the resources marshalled to supplement those services. Individuals and organisations mobilised following natural disasters need to be strengthened by enhancing the capacity of support service workers to identify and manage psychological distress in their clients.

Chromosomal and genetic analysis of the electrophoretic karyotype of Trichoderma reesei: mapping of the cellulase and xylanase genes.

An electrophoretic karyotype has been established for Trichoderma reesei strain QM6a, and several of its derivatives, by pulsed-field gel electrophoresis. All strains examined appear to have seven chromosomes with a total genome size of approximately 33 megabases (Mb). The sizes of the chromosomal bands in strain QM6a are approximately 6.2, 6.0, 5.1, 4.2 (doublet), 3.6 and 3.2 Mb. Genes encoding the cellulase complex and xylanases of T. reesei have been mapped, as have several other genes.

Altered steady-state levels of the messenger RNAs for c-myc and p53 in L1210 cell lines resistant to deoxyadenosine.

L1210 cell lines, selected for resistance to deoxyadenosine due to the loss of allosteric inhibition of ribonucleotide reductase by dATP, had altered steady-state levels of the mRNAs for c-myc, fos, and p53. Wild-type L1210 cells had constitutive steady-state levels of c-myc and p53 with little or no fos mRNA. Two different deoxyadenosine-resistant cell lines (Y8 and ED2) had elevated steady-state levels of c-myc and fos but essentially no p53 mRNA. Hydroxyurea-resistant L1210 cells had the same levels of c-myc, fos, and p53 as the wild-type cells. There was no amplification of the gene for c-myc in the Y8 or ED2 cell lines. The half-life for c-myc mRNA was essentially the same in the wild-type and the Y8 and ED2 cells. Nuclear runoff experiments showed that the rates of transcription for c-myc in the Y8 and ED2 cells were elevated and could account for the increased steady-state levels of c-myc in these two cell lines. The transcription rate for p53 mRNA was not decreased in the Y8 and ED2 cells and therefore did not account for the loss of the steady-state levels of p53 in the cells. Cycloheximide treatment of the Y8 and ED2 cells resulted in a marked increase in the steady-state p53 mRNA level, indicating that a protein which was rapidly turned over was responsible for the extremely short half-life of p53 mRNA in these two cell lines.

Factors affecting the mRNA levels for the non-heme iron and effector-binding subunits of ribonucleotide reductase.

Ribonucleotide reductase which catalyzes the rate-limiting step in the de novo synthesis of dNTPs is composed of two non-identical protein subunits which are not under coordinate control in terms of synthesis and degradation. The mRNAs for the effector-binding (EB) and non-heme iron (NHI) subunits are likewise not under coordinate control during cell cycle traverse. Inhibitors directed at the specific subunits of ribonucleotide reductase block DNA synthesis. These current studies show that drugs such as IMPY or hydroxyurea which specifically inhibit the NHI subunit cause a marked increase in the steady-state level of the mRNA for the NHI subunit while resulting in a decrease in the level of mRNA for the EB subunit. In cells treated with deoxyadenosine, the patterns of the mRNAs for the NHI and EB subunits were different from those seen in the IMPY- or hydroxyurea-treated cells. Control experiments utilizing inhibitors (aphidicolin or araC) directed at DNA polymerase showed that the pattern of changes in the mRNA levels for the NHI and EB subunits were specific for the reductase inhibitors. These changes in the mRNAs for the NHI and EB subunits may be due to drug-induced alterations in transcription rates and/or degradation rates for the specific mRNAs.

Commercial levels of chymosin production by Aspergillus.

We have increased the production of bovine chymosin in Aspergillus niger var. awamori to more than one gram per liter of secreted authentic enzyme by combining a mutagenesis protocol with a novel robotic screening program. Analysis of the superior chymosin producing strains indicated that they have enhanced capabilities to secrete extracellular proteins.