Common mental disorder and suicidality among doctors: differences by specialty.

BACKGROUND: Common mental disorders (CMDs) and suicidal ideation (SI) are prevalent among doctors, yet limited evidence exists investigating the relationship of specialty area to these outcomes. AIMS: This study aimed to determine the prevalence of likely CMD and SI among doctors and to investigate whether likelihood of these outcomes varied by area of medical specialty. METHODS: A secondary analysis of a representative national survey of 12,252 Australian doctors was conducted. Demographic and work-related variables, SI and CMD (GHQ-28), were assessed among doctors (n = 7037; 57%) working in a range of specialty areas. Logistic regression was used to examine the association between specialty and mental health outcomes in unadjusted and adjusted models. RESULTS: Almost one-quarter of doctors (n = 1560; 23%) reported symptom levels indicating likely CMD whilst 9% (n = 667) reported SI in the last year. Doctors in surgery (adjusted odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.54-0.97, P = 0.03) were at significantly lower risk of CMD than General Practitioners (GPs), whilst doctors in anaesthetics (adjusted OR = 1.45; 95% CI 1.09-1.93, P = 0.01) and paediatrics (adjusted OR = 1.88; 95% CI 1.02-3.47, P = 0.04) were at significantly higher risk of experiencing SI compared to GPs after accounting for confounders. CONCLUSIONS: Results demonstrated that doctors in Australia working in certain specialties, specifically anaesthetics and paediatrics, were at significantly greater risk of suicidal ideation compared to GPs after accounting for confounders. Interventions to address CMD and SI among doctors in all specialties remain urgently needed.

Trends and characteristics in barbiturate deaths Australia 2000-2019: a national retrospective study.

INTRODUCTION: There have been increasing reports documenting barbiturate-related deaths, despite routine prescribing for only relatively rare indications. The aims of the current study were to examine trends in barbiturate-related deaths in Australia from 2000 to 2019 and determine the case characteristics and circumstances of barbiturate-related deaths. METHODS: All barbiturate-related deaths identified in the Australian National Coronial Information System were examined. Information was collected on cause, manner, demographics, location, psychosocial factors, circumstances of deaths and toxicology. We examined these based on the age categories 18-44 years, 45-64 years and ≥65 years. RESULTS: We identified 511 cases. Mean age was 57.9 years (SD 20.2, range 18-100) and 56% were male. Intentional poisoning was the most common cause of death (87.5%) and was slightly higher in the oldest age group (92.1%) and lowest in the youngest age group (81.1%). Pentobarbitone was the most common barbiturate (75.7%) and pentobarbitone-related deaths increased from 0% in 2000 to 93.6% in 2017. There were notable differences between age categories, with the youngest age group recording more severe psychiatric histories. In contrast, the oldest age group were more likely to have severe physical health problems, such as cancer, chronic non-cancer pain, neurological conditions and significant cardiopulmonary morbidity. Euthanasia resources were commonly documented (33.9%), most frequently in the oldest age group (52.3%). CONCLUSION: Barbiturate-related deaths in Australia are increasing, particularly pentobarbitone-related deaths. Most deaths were intentional and involved adults across the lifespan. Younger people were more likely to have significant mental health problems, whilst the oldest age group were more likely to have severe physical health conditions.

Data-informed targets for suicide prevention: a small-area analysis of high-risk suicide regions in Australia.

PURPOSE: To investigate small-area variation in risks associated with suicide deaths across four regional communities in New South Wales, Australia, and to determine whether these areas have unique demographic and socioeconomic risk profiles that could inform targeted means restriction suicide prevention efforts. METHODS: Archival data on suicide mortality for all deaths in New South Wales, Australia, over the period 2006-2015 were geospatially attributed to four high-risk priority regions. Deaths in the four regions were compared to each other, and to NSW, on demographic factors, indicators of economic deprivation, and suicide means. RESULTS: Priority means restriction targets were identified for all sites. In Murrumbidgee, suicide deaths were significantly more likely to involve firearms and older males (p < 0.001). The Central Coast had a greater proportion of overdose deaths (p < 0.001), which were associated with being female and unemployed. Suicide deaths in Newcastle were associated with being younger (p = 0.001) and involving 'jumping from a height' (p < 0.001), while economic deprivation was a major risk for suicide death in Illawarra Shoalhaven (p < 0.001). CONCLUSIONS: Local regions were significantly differentiated from each other, and from the State, in terms of priority populations and means of suicide, demonstrating the need for locally based, targeted interventions. There were, however, also some risk constancies across all sites (males, hanging, economic deprivation), suggesting that prevention initiatives should, optimally, be delivered within multilevel models that target risk commonalities and provide tailored initiatives that address risk specific to a region.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

The use of paracetamol (acetaminophen) among a community sample of people with chronic non-cancer pain prescribed opioids.

BACKGROUND: The regular use of simple analgesics in addition to opioids such as paracetamol (or acetaminophen) is recommended for persistent pain to enhance analgesia. Few studies have examined the frequency and doses of paracetamol among people with chronic non-cancer pain including use above the recommended maximum daily dose. AIMS: To assess (i) the prevalence of paracetamol use among people with chronic non-cancer pain prescribed opioids, (ii) assess the prevalence of paracetamol use above the recommended maximum daily dose and (iii) assess correlates of people who used paracetamol above the recommended maximum daily dose including: age, gender, income, education, pain severity and interference, use of paracetamol/opioid combination analgesics, total opioid dose, depression, anxiety, pain self-efficacy or comorbid substance use, among people prescribed opioids for chronic non-cancer pain. METHODS: This study draws on baseline data collected for the Pain and Opioids IN Treatment (POINT) study and utilises data from 962 interviews and medication diaries. The POINT study is national prospective cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited from randomly selected pharmacies across Australia. RESULTS: Sixty-three per cent of the participants had used paracetamol in the past week (95% CI = 59.7-65.8). Among the paracetamol users 22% (95% CI = 19.3-24.6) had used paracetamol/opioid combination analgesics and 4.8% (95% CI = 3.6-6.3) had used paracetamol above the recommended maximum daily dose (i.e. > 4000 mg/day). Following binomial logistic regression (χ(2) = 25.98, df = 10, p = 0.004), people who had taken above the recommended maximum daily dose were less likely to have low income (AOR = 0.52, 95% CI = 0.27-0.99), more likely to use paracetamol/opioid combination analgesics (AOR = 2.01, 95% CI = 1.02-3.98) and more likely to take a higher opioid dose (AOR = 1.00, 95% CI = 1.00-1.01). CONCLUSION: The majority of people with chronic non-cancer pain prescribed opioids report using paracetamol appropriately. High income, use of paracetamol/opioid combination analgesics and higher opioid dose were independently associated with paracetamol use above the recommended maximum daily dose.

In vitro and in vivo evidence for anti-inflammatory properties of 2-methoxyestradiol.

2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17ß-estradiol that interacts with estrogen receptors and microtubules. It has acute anti-inflammatory activity in animal models that is not attributable to known antiproliferative or antiangiogenic actions. Because macrophages are central to the innate inflammatory response, we examined whether suppression of macrophage activation by 2MEO could account for some of its anti-inflammatory effects. Inflammatory mediator production stimulated by lipopolysaccharide (LPS) and interferon-γ in the J774 murine macrophage cell line or human monocytes was measured after treatment with 2MEO or the anti-inflammatory agent dexamethasone. The effect of these agents on LPS-induced acute lung inflammation in mice was also examined. 2MEO suppressed J774 macrophage interleukin-6 and prostaglandin E2 production (by 30 and 47%, respectively, at 10 µM) and human monocyte tumor necrosis factor-α production (by 60% at 3 µM). Estradiol had no effect on J774 macrophage activation, nor did the estrogen receptor antagonist 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17ß-diol (ICI 182,780) prevent the effects of 2MEO. The actions of 2MEO were not mimicked by the microtubule-interfering agents colchicine or paclitaxel. In mice exposed to LPS, bronchoalveolar lavage protein content, a measure of vascular leak and epithelial injury, was reduced to a comparable extent (~54%) by treatment with 2MEO (150 mg · kg⁻¹) or dexamethasone (1 mg · kg⁻¹). In addition, 2MEO reduced LPS-induced interleukin-6 gene expression. Thus, 2MEO modulates macrophage activation in vitro and has high-dose acute anti-inflammatory activity in vivo. These findings are consistent with the acute anti-inflammatory actions of 2MEO being mediated in part by the suppression of macrophage activation.

Concanavalin A-induced alteration of surface marker expression on murine T cells.

The activation of suppressor T cells by Concanavalin A (Con A) was characterized by changes in expression of T cell surface markers. Treatment of normal mouse spleen cells with monoclonal antibody to Ly-1 prior to activation with Con A consistently reduced the resulting suppressor cell activity as assayed by mixed culture with primed spleen cells responding to sheep erythrocytes. Addition of indomethacin to anti-Ly-1 depleted spleen cells together with Con A had no effect on the resulting suppressor cell activity, whereas its addition to normal spleen cells together with Con A significantly abrogated suppressor T cell induction. In contrast, treatment of normal spleen cells with anti-Ly-1 following 24h culture with Con A had no effect on resulting suppressor cell activity. Treatment of spleen cells either prior to or following culture with Con A with monoclonal antibody to Ly-2 completely abrogated suppressor T cell activity. Suppressor T cells activated by Con A were depleted significantly by fractionation on columns containing insolubilized histamine. In contrast, fractionation of normal spleen cells on histamine columns followed by culture with Con A had no effect on subsequent suppressor T cell induction. Furthermore, direct addition of histamine (5 x 10(-4) M - 5 x 10(-8) M) to Con A preculture had no effect on resultant suppressor T cell generation, suggesting that possible immunodulatory actions of histamine may be expressed at the effector rather than during induction stages of Con A-induced suppressor T cell activation.

Abrogation of suppressor cell function by inhibitors of prostaglandin synthesis.

The weekly intraperitoneal injection of rat erythrocytes into mice induces both a stable autoimmune state, as judged by the appearance of anti-mouse erythrocyte autoantibody and suppressor T cells capable of regulating this response; the latter being demonstrable only in a subsequent transfer system. This autoimmune response and the parallel anti-rat erythrocyte response were both insensitive to exogenous prostaglandin E2 (PGE2). The administration of prostaglandin synthetase inhibitors (indomethacin or aspirin) to mice undergoing immunization with rat erythrocytes had no effect on the anti-rat response, yet mildly exacerbated the onset of the autoimmune state and potently inhibited the generation of suppressor cells. Furthermore the administration of these drugs to recipients of suppressor cells virtually abrogated suppressor cell activity. These observations imply that both the generation and effector function of these suppressor cells may be modulated by prostaglandin synthetase inhibitors while at the same time T helper and B cell functions remain unimpaired.

Attenuation of murine graft-versus-host reactivity by azathioprine.

The therapeutic effects of azathioprine were evaluated in a murine graft-versus-host (GVH) model. A single high dose (200 mg/kg) of azathioprine, administered to F1 recipients 2 to 3 days after the injection of parental spleen cells, abrogated the ensuing GVH reaction. Lower doses of the drug, even when injected over an extended period of time (14 days), were found to be ineffective. However, high doses of azathioprine failed to protect when F1 recipients were sublethally irradiated or injected with cyclophosphamide before GVH induction, and even the transfer of syngeneic F1 spleen cells immediately after irradiation failed to alter this outcome. Further analysis of the changes that occurred in sublethally irradiated recipients revealed that the protective effect of azathioprine on CBA leads to (CBA x C57BL)F1 GVH reaction was totally abrogated by doses of irradiation as low as 200 rad. Further experiments in which death was used as an indicator of GVH disease showed that lethality could not be reversed in sublethally irradiated F1 recipients by the transfer of syngeneic F1 spleen cells unless approximately 10 days were allowed to elapse between syngeneic reconstitution and GVH induction. Since syngeneic F1 cells from spleen, lymph node, or bone marrow all behaved similarly, it seems likely that the increased severity of GVH reaction induced by prior immunosuppression may not be attributable to a simple cell deletion event.

The induction of suppressor T cells by concanavalin A is independent of cellular proliferation and protein synthesis.

Factors that govern the induction of suppressor T cells after stimulation with concanavalin A (Con A) were investigated in a two-stage culture system. Normal mouse spleen cells were incubated with Con A in the presence of a variety of drugs and then assayed for suppressive activity by means of a secondary anti-sheep erythrocyte response in vitro. The inclusion of inhibitors of mitosis (vinblastine sulphate or mytomycin C) or protein synthesis (cycloheximide or pactamycin) into normal spleen cell cultures containing Con A failed to inhibit the subsequent development of suppressor cells. Furthermore, spleen cells from mice previously irradiated with 900 rad or injected with cyclophosphamide expressed a level of suppressor activity after Con A stimulation which was equivalent to that of normal spleen cells. However, the inclusion of drugs that inhibit microtubule or microfilament function (colchicine or cytocholasin B) did prevent suppressor cell induction. Kinetic studies also revealed that significant suppressor activity was detectable in normal spleen cells after only 3 h exposure to Con A. These results indicate that the induction of suppressor T cells in this system is a maturation event involving changes in the cell membrane and is entirely independent of protein synthesis and cellular proliferation.

The capacity of microsomally-activated cyclophosphamide to induce immunosuppression in vitro.

Cyclophosphamide (CY) was activated in vitro with washed rat liver microsomes and cofactors. Pretreatment of mouse spleen cells in vitro with the activated drug abolished their capacity to give a primary antibody response to SRBC and levan on transfer to irradiated syngeneic recipients. However, responsiveness returned if challenge was delayed for 7 or more days after transfer. Part of this was shown to be of donor origin by an allotype marker. The treatment of normal spleen cells with activated CY in vitro also prevented B cells from regenerating their immunoglobulin receptors after capping with anti-immunoglobulin serum. The induction of suppression required contact between lymphocytes and activated CY for at least 30 min at 37 degrees and did not appear following incubation for 1 h at 0 degrees. Since the antibody response of drug-treated spleen cells to SRBC could not be restored with purified normal B or T cells, it is probable that B and T lymphocytes are both susceptible to suppression by activated CY in vitro. Similar pretreatment abrogated the graft-versus-host (GVH) reactivity of spleen cells as measured by survival and in a popliteal lymph node assay. B cell chimerism in F1 recipients of drug-treated parental spleen cells was demonstrated by the presence of congenic allotype markers. This suggests a possible approach for the attenuation of GVH disease which is associated with bone marrow transplantation in man.

Ly and Ia phenotype of suppressor T cells induced by graft-vs.-host reaction.

Suppressor T cells were generated in (CBA X C57BL)F1 mice undergoing graft-vs.-host (GvH) reaction and treated with anti-Ly and anti-Ia antisera to determine their membrane antigen phenotype. Pretreatment of CBA-induced GvH suppressor T cells with anti-Ly-1.1, anti-Ly-2.1 or anti-Iak antisera plus complement abrogated their suppressive properties when tested against primed F1 spleen cells in vitro. In contrast, concanavalin A (Con A)-induced suppressor T cells were insensitive to anti-Ly-1.1 serum. It is concluded that GvH-induced suppressor T cells are Ly-1+,2+,3+,Ia+, and thus distinct from Con A or antigen-induced suppressor T cells.

The adoptive secondary response to human serum albumin under conditions of high antigen pressure. The response of high and low avidity B cell subsets.

Thoracic duct lymphocytes (TDL) from (AS2 x AS)F1 rats previously injected with human serum albumin (HSA) were transferred to 900 r irradiated syngeneic recipients which were challenged with various doses of soluble HSA (s-HSA). TDL from partially tolerant rats, which were deficient in high avidity B cells, produced a maximum PFC response to the largest challenge dose (1 g s-HSA). In contrast, high avidity B cells from primed donors were optimally stimulated by 1 microgram and maximally inhibited by 1 mg s-HSA (day 7 PFC). An additional increase in antigen concentration by 1000 fold failed to diminish the PFC numbers further. Plaque inhibition profiles indicated that these antibody forming cells resisting inhibition were of the same high avidity as those triggered by low doses of antigen. The inability of s-HSA to completely inhibit antibody synthesis is discussed with regard to current views on B cell inactivation. Evidence is also presented which indicates that the standard haemolysis-in-gel test may fail to detect many low avidity antibody forming cells to proteins.

Cellular events in protein-tolerant inbred rats. IV. The mechanism of immunogen-maintained tolerance.

The ability of immunogens to maintain or extend a state of unresponsiveness was investigated in unbred rats using a human serum albumin (HSA) model of tolerance. Rats initially challenged with immunogen within two weeks of high or low dose tolerance induction by tolerogen (soluble HSA) remained hyporesponsive even a year and a half later and in some cases became less responsive following a subsequent challenge. An inhibitory effect of immunogen on escape from tolerance was formally demonstrated: in comparison with an unchallenged group, tolerant rats which received a second immunogen challenge 6 months after the first, synthesized less antibody; this antibody underwent a gradual decline in affinity after each challenge which suggested that higher avidity B cells were progressively lost. In addition, immunogen-maintained tolerant rats (a) had demonstrable helper T cell activity among their thoracic duct lymphocytes on adoptive transfer, (b) did not produce a significant increase in antibody synthesis after receiving peripheral T cells and (c) provided no evidence that suppressor cells were playing a role. The results suggested that the mechanisms of tolerance induction by tolerogen and tolerance maintenance by immunogen are fundamentally different.