'Everything was just getting worse and worse': deteriorating job quality as a driver of doctor emigration from Ireland.

BACKGROUND: Medicine is a high-status, high-skill occupation which has traditionally provided access to good quality jobs and relatively high salaries. In Ireland, historic underfunding combined with austerity-related cutbacks has negatively impacted job quality to the extent that hospital medical jobs have begun to resemble extreme jobs. Extreme jobs combine components of a good quality job-high pay, high job control, challenging demands, with those of a low-quality job-long working hours, heavy workloads. Deteriorating job quality and the normalisation of extreme working is driving doctor emigration from Ireland and deterring return. METHODS: Semi-structured qualitative interviews were conducted with 40 Irish emigrant doctors in Australia who had emigrated from Ireland since 2008. Interviews were held in July-August 2018. RESULTS: Respondents reflected on their experiences of working in the Irish health system, describing hospital workplaces that were understaffed, overstretched and within which extreme working had become normalised, particularly in relation to long working hours, fast working pace, doing more with less and fighting a climate of negativity. Drawing on Hirschman's work on exit, voice and loyalty (1970), the authors consider doctor emigration as exit and present respondent experiences of voice prior to emigration. Only 14/40 respondent emigrant doctors intend to return to work in Ireland. DISCUSSION: The deterioration in medical job quality and the normalisation of extreme working is a key driver of doctor emigration from Ireland, and deterring return. Irish trained hospital doctors emigrate to access good quality jobs in Australia and are increasingly likely to remain abroad once they have secured them. To improve doctor retention, health systems and employers must mitigate a gainst the emergence of extreme work in healthcare. Employee voice (about working conditions, about patient safety, etc.) should be encouraged and used to inform health system improvement and to mitigate exit.

The evolution of methods for urinary steroid metabolomics in clinical investigations particularly in childhood.

The metabolites of cortisol, and the intermediates in the pathways from cholesterol to cortisol and the adrenal sex steroids can be analysed in a single separation of steroids by gas chromatography (GC) coupled to MS to give a urinary steroid profile (USP). Steroids individually and in profile are now commonly measured in plasma by liquid chromatography (LC) coupled with MS/MS. The steroid conjugates in urine can be determined after hydrolysis and derivative formation and for the first time without hydrolysis using GC-MS, GC-MS/MS and liquid chromatography with mass spectrometry (LC-MS/MS). The evolution of the technology, practicalities and clinical applications are examined in this review. The patterns and quantities of steroids changes through childhood. Information can be obtained on production rates, from which children with steroid excess and deficiency states can be recognised when presenting with obesity, adrenarche, adrenal suppression, hypertension, adrenal tumours, intersex condition and early puberty, as examples. Genetic defects in steroid production and action can be detected by abnormalities from the GC-MS of steroids in urine. New mechanisms of steroid synthesis and metabolism have been recognised through steroid profiling. GC with tandem mass spectrometry (GC-MS/MS) has been used for the tentative identification of unknown steroids in urine from newborn infants with congenital adrenal hyperplasia. Suggestions are made as to areas for future research and for future applications of steroid profiling. As routine hospital laboratories become more familiar with the problems of chromatographic and MS analysis they can consider steroid profiling in their test repertoire although with LC-MS/MS of urinary steroids this is unlikely to become a routine test because of the availability, cost and purity of the internal standards and the complexity of data interpretation. Steroid profiling with quantitative analysis by mass spectrometry (MS) after chromatography now provides the most versatile of tests of adrenal function in childhood.

A Direct Oral Anticoagulant as a Cost Effective Alternative to Warfarin for Treatment of Provoked Venous Thrombosis.

In Ireland, Warfarin is the primary anticoagulant prescribed in the secondary prevention of provoked DVT. We completed a comprehensive cost analysis of a trial group of 24 patients treated with Rivaroxaban (between November 2013 and December 2014), versus a control group treated with Warfarin (between January 2008 and November 2013). The groups were matched for gender (3/7 M/F ratio), DVT type (5 proximal, 19 distal DVTs), provoking factor (20 traumatic, 4 atraumatc), and age. We calculated the cost for each group based on drug administration and clinic costs (labour, sample analysis, and additional costs). Warfarin patients attended clinic 14.58 times; Rivaroxaban patients attended 2.92 times. Overall, the cost per patient on Rivaroxaban is €273.30 versus €260.68 with warfarin. This excludes patient costs which would further increase cost of Warfarin therapy.

Reincarnation of ancient links between coagulation and complement.

Throughout evolution, organisms have developed means to contain wounds by simultaneously limiting bleeding and eliminating pathogens and damaged host cells via the recruitment of innate defense mechanisms. Disease emerges when there is unchecked activation of innate immune and/or coagulation responses. A key component of innate immunity is the complement system. Concurrent excess activation of coagulation and complement - two major blood-borne proteolytic pathways - is evident in numerous diseases, including atherosclerosis, diabetes, venous thromboembolic disease, thrombotic microangiopathies, arthritis, cancer, and infectious diseases. Delineating the cross-talk between these two cascades will uncover novel therapeutic insights.

Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses.

BACKGROUND: The plasmin(ogen) and complement systems are simultaneously activated at sites of tissue injury, participating in hemostasis, wound healing, inflammation and immune surveillance. In particular, the C3 proteolytic fragment, iC3b, and its degradation product C3dg, which is generated by cleavage by factor I (FI) and the cofactor complement receptor CR1, are important in bridging innate and adaptive immunity. Via a thioester (TE) bond, iC3b and C3dg covalently tag pathogens, modulating phagocytosis and adaptive immune responses. OBJECTIVE: To examine plasmin-mediated proteolysis of iC3b, and to evaluate the functional consequences, comparing the effects with products generated by FI/CR1 cleavage of iC3b. METHODS: Dose-dependent and time-dependent plasmin-mediated cleavage of iC3b were characterized by analytical gel electrophoresis. The properties of the resultant TE bond-containing fragments on phagocytosis and induction of pro-inflammatory cytokines were measured in cell culture systems. RESULTS: At low concentrations, plasmin effectively cleaves iC3b, but at numerous previously undescribed sites, giving rise to novel C3c-like and C3dg-like moieties, the latter of which retain the TE bond. When attached to zymosan or erythrocytes and exposed to THP-1 macrophages, the C3dg-like proteins behave almost identically to the bona fide C3dg, yielding less phagocytosis as compared with the opsonin iC3b, and more macrophage secretion of the pro-inflammatory cytokine, IL-12. CONCLUSION: Plasmin cleavage of iC3b provides a complement regulatory pathway that is as efficient as FI/CR1 but does not require a cellular cofactor.

Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1.

The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs, and Survivin deletion in mice resulted in significantly reduced total marrow HSCs and hematopoietic progenitor cells. Transcriptional analysis of Survivin(-/-) HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin -/- HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1 transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.

An unanticipated role for survivin in organ transplant damage.

Ischemia/reperfusion (I/R) injury is a major determinant of graft survival in kidney transplantation. Survivin, an inhibitor of apoptosis that participates in the control of mitosis and cell cycle progression, has been implicated in renal protection and repair after I/R injury; however, no study has been performed in the transplant setting. We investigated the role of survivin in modulating posttransplant I/R injury in syngeneic and allogeneic kidney grafts, and studied whether protection from I/R injury impacted on the recipient immune system, on chronic allograft nephropathy and rejection. We used genetically engineered mice with survivin haploinsufficiency and WT mice in which survivin over-expression was induced by gene-delivery. Survivin haploinsufficiency in syngeneic grafts was associated with exuberant I/R tissue injury, which triggered inflammation eventually resulting in graft loss. Conversely, survivin over-expression in the grafts minimized I/R injury and dysfunction in syngeneic grafts and in a clinically relevant fully MHC-mismatched allogeneic combination. In the latter, survivin over-expression translated into limited anti-donor adaptive immune response and less long-term allograft injury with protection from renal parenchymal damage. Our data support survivin over-expression in the graft as a novel target for protocols aimed at limiting tissue damage at the time of transplant ultimately modulating the recipient immune system.

Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia.

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/ß- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.

Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function.

The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis.

Loss of survivin in neural precursor cells results in impaired long-term potentiation in the dentate gyrus and CA1-region.

In adult mammals, newborn neural precursor cells (NPCs) derived from either the subventricular zone (SVZ) or the subgranular zone (SGZ) migrate into the olfactory bulb and the dentate gyrus (DG), respectively, where some of them mature into excitatory and inhibitory neurons. There is increasing evidence that this neurogenesis process is important for some types of learning and synaptic plasticity and vice versa. Survivin, a member of the inhibitor-of-apoptosis protein (IAP) family, has been suggested to have a central role in the regulation of neurogenesis. The protein is abundantly expressed in nervous tissue during embryonic development while being restricted postnatally to proliferating and migrating NPCs in SVZ and SGZ. Here we examined adult Survivin(Camcre) mice with a conditional deletion of the survivin gene in embryonic neurogenic regions. Although the deletion of survivin had no effect on basic excitability in DG and CA1-region, there was a marked impairment of long-term potentiation (LTP) in these areas. Our data support a function of survivin in hippocampal synaptic plasticity and learning and underline the importance of adult brain neurogenesis for proper operation of the hippocampal tri-synaptic circuit and the physiological functions that depend on it.

Examining IQ among a clinical sample of preschool children with autism spectrum disorder over time.

BACKGROUND: The cognitive functioning of children who received a diagnosis of autistic spectrum disorder (ASD) during the preschool years was assessed at the time of diagnosis (Time 1) and reassessed, on average, 3 years and 5 months later (Time 2). METHOD: A total of 50 children were assessed (76% male, n = 38); the group had an average age of 4 years 3 months at Time 1 and 7 years 8 months at Time 2. RESULTS: There was a significant positive relationship (r = 0.791, p < 0.01) between the group's Full Scale Intelligence Quotient (FSIQ)/Developmental Quotient (DQ) at Time 1 and at Time 2. Results indicated a significant increase in FSIQ/DQ over time for the total group and for both the High Functioning (IQ ⩾ 70) and Low Functioning (IQ < 70) groups. Of the total samples, 32% showed a clinically significant change in FSIQ/DQ of 15 points or more from Time 1 to Time 2. When age at Time 1 was included as a covariate, no significant difference was identified for change in FSIQ over time. The practical implications of the findings are discussed.

Geographical clustering of anal cancer incidence in Australia.

INTRODUCTION: Homosexual men are at an increased risk of anal cancer. We aimed to establish the burden of anal squamous cell carcinoma (SCC) in those parts of Australia where homosexual men are most likely to live. METHODS: Data on the proportion of homosexual male residents were obtained from published estimates. Men were categorised into three postcode groups by prevalence of men reporting homosexual identity. Male population data in age groups were extracted for each postcode group and analyses of cancer incidence were performed by postcode group. The analyses were restricted to 2000-2005. RESULTS: Eight postcodes had populations where more than 10% of males reported homosexual identity (high prevalence) and 4-10% of men reported homosexual activity in a further 19 postcodes (medium prevalence). From 2000 to 2005, the average annual age-standardised incidence rates of anal SCC in males was 7.61 per 100000 (95% confidence interval (CI): 4.68-10.55) and 2.21 per 100000 (95% CI: 1.05-3.37) in high and medium prevalence postcodes, respectively. The corresponding incidence rate ratios compared with low prevalence postcodes (less than 4% of males reported homosexual identity) were 9.6 (95% CI: 6.6-14.1) for the high prevalence and 2.4 (95% CI: 1.4-4.1) for the medium prevalence postcodes. CONCLUSION: A substantial concentration of the burden of anal cancer occurred among areas where large proportions of homosexual men reside. These results should guide the prioritisation of health service investment in anal cancer treatment and prevention to appropriate geographical areas.

Quality of life valuations of HPV-associated cancer health states by the general population.

OBJECTIVES: To obtain health-related quality of life valuations (ie, utilities) for human papillomavirus (HPV)-related cancer health states of vulval, vaginal, penile, anal and oropharyngeal cancers for use in modelling cost-effectiveness of prophylactic HPV vaccination. METHODS: Written case descriptions of each HPV-associated cancer describing the 'average' patient surviving after the initial cancer diagnosis and treatment were developed in consultation with oncology clinicians. A general overview, standard gamble questionnaire for each health state and a quiz was conducted in 120 participants recruited from the general population. RESULTS: In the included population sample (n=99), the average age was 43 years (range = 18-70 years) with 54% men, 44% never married/43% married, 76% education beyond year 12 and 39% employed full-time. The utility values for the five health states were 0.57 (95% CI 0.52 to 0.62) for anal cancer, 0.58 (0.53 to 0.63) for oropharyngeal cancer, 0.59 (0.54 to 0.64) for vaginal cancer, 0.65 (0.60 to 0.70) for vulval cancer and 0.79 (0.74 to 0.84) for penile cancer. Participants demonstrated a very good understanding of the symptoms, diagnosis and treatment of these cancers with a mean score of 9 (SD=1.1) on a 10-item quiz. CONCLUSIONS: This study provides utility estimates for the specific HPV-related cancers of vulval, vaginal, penile, anal and oropharyngeal cancers valued by a general population sample using standard gamble. The results demonstrate considerable quality of life impact associated with surviving these cancers that will be important to incorporate into modelling cost-effectiveness of prophylactic HPV vaccination in different populations.

Head and neck cancer in Australia between 1982 and 2005 show increasing incidence of potentially HPV-associated oropharyngeal cancers.

BACKGROUND: Although tobacco- and alcohol-associated head and neck cancers are declining in the developed world, potentially human papillomavirus (HPV)-associated oropharnygeal cancers are increasing. METHODS: We analysed oropharyngeal and oral cavity cancer rates in Australia in 1982-2005. Cancers from the oropharynx (base of tongue, tonsil and other specific oropharyngeal sites) were classified as potentially HPV associated (n=8844); cancers in other oral cavity and oropharyngeal sites not previously associated with HPV were classified as comparison (n=28,379). RESULTS: In 2000-2005, an average of 219, 159 and 110 cancers of the tonsil, base of tongue and other oropharyngeal sites were diagnosed annually, with incidences of 1.09 (95% CI: 1.03, 1.15), 0.79 (95% CI: 0.74, 0.84) and 0.55 (95% CI: 0.50, 0.59) per 100,000, respectively. An average of 1242 comparison cancers were diagnosed annually (6.17 (95% CI: 6.03, 6.31) per 100,000). In 1982-2005, there were significant annual increases in tonsil (1.39% (95% CI: 0.88, 1.92%)) and base of tongue cancers in males (3.02% (95% CI: 2.27, 3.78%)) and base of tongue cancer in females (3.45% (95% CI: 2.21, 4.70%)). There was a significant decrease in comparison cancers in men (-1.69% (95% CI: -1.96, -1.42%)), but not in females. CONCLUSION: Potentially HPV-associated oropharyngeal cancer in Australia is increasing; the impact of HPV vaccination on these cancers should be monitored.

Trends in anal cancer in Australia, 1982-2005.

BACKGROUND: Most anal squamous cell carcinomas (SCCs) are caused by high risk types of human papillomavirus (HPV) and are potentially preventable by HPV vaccination. In order to understand the burden of potentially preventable anal cancer in Australia, we examine the incidence and survival from invasive anal SCC 1982-2005. METHODS: We reviewed data on invasive anal cancer cases notified to the National Cancer Statistics Clearing House. Age specific incidence rates of SCC were calculated by year of cancer diagnosis and by birth cohort, and rates of anal adenocarcinoma were included for comparison. Incidence rates were age standardised to the Australian 2001 standard population. Trends in relative survival of SCC were examined. RESULTS: During the study period, a total of 4615 invasive anal cancer cases were diagnosed and most (69.7%) were SCC. Annual incidence of SCC increased almost 50%, from 0.65 to 1.00/100,000. Incidence increased at all ages. The annual rate of increase was almost two-folder higher in men (3.42%, 95% CI 2.49-4.35) than in women (1.88%, 95% CI 1.18-2.58). Five-year relative survival increased by nearly 10% from 58.9% to 68.3% over the last 20 years. Younger patients and women had better survival. For anal adenocarcinoma, increases of borderline significance were seen in men and women. CONCLUSION: There is an increasing burden of anal SCC in Australia. The group with the highest incidence - homosexual men - are not likely to be protected under the current vaccination policy.

Cancers attributable to human papillomavirus infection.

Although the human papillomavirus (HPV) vaccine was introduced primarily as a cervical cancer prevention vaccine, HPV has a causal role in several types of cancer. This article reviews the epidemiological evidence for the role of HPV in human cancer, and describes Australian trends in these cancers. HPV is a necessary cause of cervical cancer. The currently vaccine-preventable subtypes of HPV 16 and 18 are responsible for ~70% of cervical cancer. The introduction of an organised Pap smear program in Australia led to a steep decline in incidence over the past decades. HPV can be detected in ~40% and 70% of vulval and vaginal cancers respectively. Rates of these cancers have been stable over the past 20 years. The prevalence of HPV in penile cancer is ~50% and incidence has not recently changed. For anal cancer, ~85% of cases are HPV positive, and incidence has increased significantly in both men and women over the past 20 years. In the oral cavity, ~35% of oropharyngeal cancers and ~25% of other oral cavity cancers are HPV positive. The incidence of HPV-related oral cavity and oropharyngeal cancers is increasing, whereas incidence at HPV-unrelated sites is decreasing. Overall, 1154 HPV-related cancer cases were potentially preventable by vaccination. If HPV-related cancers at non-cervical sites are prevented by vaccination, then a similar number of cancer cases will be prevented as in the cervix. However, almost one-quarter of the potentially preventable cancer cases are in men, who are not included in the current national immunisation program.

Genital warts incidence and healthcare resource utilisation in Australia.

OBJECTIVES: To estimate for the first time the incidence and healthcare resource utilisation associated with genital warts (GW) in Australia prior to the human papillomavirus vaccination programme. METHOD: The authors analysed data from the nationally representative Bettering the Evaluation of Care and Health general practice cross-sectional programme and from the National Hospital Morbidity Database to estimate age-related incidence and community (non-hospital) and hospital-related costs (in 2009 Australian dollars) associated with medical treatment of GW. RESULTS: The authors estimated an annual incidence of 2.19 cases of GW per 1000 Australians (95% CI 1.88 to 2.49), with peak incidence in women aged 20-24 years at 8.61 cases per 1000 and in men aged 25-29 years at 7.40 cases per 1000. The estimated number of consultations per GW case was 2.9 (95% CI 2.5 to 3.3) for women and 2.8 (95% CI 2.3 to 3.2) for men. Ablative treatments in general practice were more common in men (60% of consultations) than in women (37% of consultations). In contrast, more women (16% vs 8%) were referred to specialists, and 75% of ablative procedures requiring hospitalisation were performed in women. The annual cost of management of GW is over A$14 million, with an estimated cost per treated case of A$251 for men and A$386 for women. CONCLUSIONS: GW impose a large health and cost burden on Australians. The national immunisation programme with the quadrivalent human papillomavirus vaccine has the potential to greatly reduce this burden, and future research measuring its impact is keenly anticipated.