Somatic mutations and clonal dynamics in healthy and cirrhotic human liver.

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

Liquid BIOpsy for MiNimal RESidual DiSease Detection in Head and Neck Squamous Cell Carcinoma (LIONESS)-a personalised circulating tumour DNA analysis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) remain a substantial burden to global health. Cell-free circulating tumour DNA (ctDNA) is an emerging biomarker but has not been studied sufficiently in HNSCC. METHODS: We conducted a single-centre prospective cohort study to investigate ctDNA in patients with p16-negative HNSCC who received curative-intent primary surgical treatment. Whole-exome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tumour tissue. We utilised RaDaRTM, a highly sensitive personalised assay using deep sequencing for tumour-specific variants, to analyse serial pre- and post-operative plasma samples for evidence of minimal residual disease and recurrence. RESULTS: In 17 patients analysed, personalised panels were designed to detect 34 to 52 somatic variants. Data show ctDNA detection in baseline samples taken prior to surgery in 17 of 17 patients. In post-surgery samples, ctDNA could be detected at levels as low as 0.0006% variant allele frequency. In all cases with clinical recurrence to date, ctDNA was detected prior to progression, with lead times ranging from 108 to 253 days. CONCLUSIONS: This study illustrates the potential of ctDNA as a biomarker for detecting minimal residual disease and recurrence in HNSCC and demonstrates the feasibility of personalised ctDNA assays for the detection of disease prior to clinical recurrence.

'People Just Need to Try It to Be Converted!': A Picture of Consumer Mental Health Research in Australia and New Zealand.

A range of barriers that impede collaborations between consumer researchers and other researchers have been identified, despite clear acknowledgement of the benefits of this approach in the literature. Recent research has questioned whether the costs of collaborative research outweigh the benefits. The overarching aim of the current study is to better understand non-consumer researchers' attitudes to, and issues concerning, engagement with consumer researchers. Non-consumer researchers from mental health disciplines were invited to participate in the cross-sectional Consumers as Researchers in Mental Health survey, and to respond to open-ended questions about their experiences of collaborative research with consumer researchers. The findings demonstrate a range of benefits associated with collaborations with consumer researchers - including increased relevance and credibility of research, and greater translation of research findings into changes in health policy, service, research and education. Collaborations were found to be varied and not limited by research design, decision-making styles, or research topic. Understanding these benefits within the context of identified barriers can make an important contribution to the proliferation of mental health consumer researcher roles.

Differences between medical school and PGY1 learning outcomes: An explanation for new graduates not being "work ready"?

Background: Widespread concerns about new medical graduates' 'work readiness' may reflect, in part, differences in mandatory learning outcomes for medical students and new medical graduates.Purpose: To examine differences between required medical student and PGY1 (first year resident) training program outcomes, and the nature and magnitude of these differences.Method: Comparison, systematic identification and thematic analysis of differences between the graduate outcomes in the Australian Medical Council Standards for the Assessment and Accreditation of Primary Medical Programs and those in the New Zealand Curriculum Framework for Prevocational Training.Results: The relationship between these outcome statements were categorized as: essentially similar; continuity; partial discontinuity; and complete discontinuity of learning trajectory. Areas requiring substantial new learning may reflect medical schools' focus on individual student performance, and on learning and assessments based on single episodes of often uncomplicated illness. This contrasted with a post-graduate focus on integrated health care delivery by teams and management of complex illnesses over the whole patient care journey.Conclusions: Characterizing these marked differences between pre-graduate and postgraduate standards, within a trajectory of learning, explains some of the difficulties in students' preparation for work readiness. These could inform learning interventions to support new graduates' professional development to ensure patient safety. Development and revision of accreditation standards should include formal review against the expectations of the preceding and succeeding phases of learning.

"Chipping away": non-consumer researcher perspectives on barriers to collaborating with consumers in mental health research.

BACKGROUND: Collaboration between researchers who have lived experience of mental illness and services (consumer researchers) and mental health researchers without (other mental health researchers) is an emergent development in research. Inclusion of consumer perspectives is crucial to ensuring the ethics, relevancy and validity of mental health research; yet widespread and embedded consumer collaboration of this nature is known to be impeded by attitudinal and organisational factors. Limited research describes consumer researchers' experiences of barriers. Other mental health researchers are key players in the co-production process yet there is also a paucity of research reporting their views on barriers to collaborating with consumers. AIMS: To explore other researchers' views and experiences on partnering with consumer mental health researchers in Australia and New Zealand. METHODS: Exploratory qualitative design. Eleven semi-structured interviews were conducted with mental health researchers. Interviews were recorded, transcribed and thematically analysed. RESULTS: Four themes concerning barriers to collaborating with consumers (hierarchies, status quo, not understanding, paternalism), and one theme on addressing the barriers (constantly chipping away) were identified. CONCLUSIONS: It is suggested that multifaceted strategies for advancing collaboration with consumers are most effective. It is imperative to attend to several barriers simultaneously to redress the inherent power disparity.

Combined bottom-up and top-down pressures drive catastrophic population declines of Arctic skuas in Scotland.

Understanding drivers of population change is critical for effective species conservation. In the northeast Atlantic Ocean, recent changes amongst seabird communities are linked to human and climate change impacts on food webs. Many species have declined severely, with food shortages, and increased predation reducing productivity. Arctic skua Stercorarius parasiticus, a kleptoparasite of other seabirds, is one such species. The aim of the study was to determine relative effects of bottom-up and top-down pressures on Arctic skuas across multiple colonies in a rapidly declining national population. Long-term monitoring data were used to quantify changes in population size and productivity of Arctic skuas, their hosts (black-legged kittiwake Rissa tridactyla, common guillemot Uria aalge, Atlantic puffin Fratercula arctica, Arctic tern Sterna paradisaea) and an apex predator (great skua Stercorarius skua) over 24 years (1992-2015) in Scotland. We used digital mapping and statistical models to determine relative effects of bottom-up (host productivity) and top-down (great skua density) pressures on Arctic skuas across 33 colonies, and assess variation between three colony types classified by host abundance. Arctic skuas declined by 81% and their hosts by 42%-92%, whereas at most colonies great skuas increased. Annual productivity declined in Arctic skuas and their hosts, and reduced Arctic skua breeding success was a driver of the species' population decline. Arctic skua productivity was positively associated with annual breeding success of hosts and negatively with great skua density. Intercolony variation suggested Arctic skua trends and productivity were most sensitive to top-down pressures at smaller colonies of host species where great skuas had increased most, whereas bottom-up pressures dominated at large colonies of host species. Scotland's Arctic skua population is declining rapidly, with bottom-up and top-down pressures simultaneously reducing breeding success to unsustainably low levels. Marine food web alterations, strongly influenced by fisheries management and climate change, are driving the decline, and this study demonstrates severe vulnerability of seabirds to rapid change in human-modified ecosystems. Potential but untested conservation solutions for Arctic skuas include marine protected areas, supplementary feeding within colonies and management of great skuas.

Mental Health Researchers' Views About Service User Research: A Literature Review.

Services users are becoming actively involved in mental health research. How this is perceived by other researchers is not well known. The aim of this article is to review the international literature exploring other mental health researchers' views of service users conducting research, between 1996 and 2016. Searches of multiple databases (PubMed, PsycINFO, CINAHL, and Google Scholar) were undertaken. Combinations of terms related to service user research and mental health researcher perspectives, views, and attitudes were used. Manual inquiry of reference lists was also undertaken. Relevant papers were coded by topic, location, study design, and other dimensions. Five articles met inclusion criteria. Most referred to perceived benefits, such as greater validity of research findings, challenges of collaborating with service users, and the validity of research findings. There was some evidence of more openness to mental health service users providing suggestions, preferably in early stages of the research process. Reluctance to co-research with service users was reported. There is limited research directly addressing other mental health researchers' views about service user research; barriers to inclusion (whether involvement, co-production or user-controlled) and creating incongruence with health policy statements. Further research to more fully understand these attitudes and how they might be influenced is warranted.

Turning the Tables: Power Relations Between Consumer Researchers and Other Mental Health Researchers.

A crucial development resulting from consumer involvement in mental health services has been engagement as active participants in mental health research, often conducted in collaboration with mental health researchers representing the health disciplines (referred to in this paper as 'other' researchers). Despite progress in mental health consumer research, unequal power relations continue to pose a major barrier. Although power issues are discussed in the literature, there is little research from the perspective of other mental health researchers who have collaborated with consumers on research projects. This qualitative study explored other mental health researchers' perspectives on the role of power in collaborative research with consumers. Semi-structured interviews were completed with 11 other mental health researchers. Thematic analysis of the transcript version of interview recordings was conducted. The findings were grounded in 'the table' as a literal and metaphorical site of power relations. The umbrella theme was prominence and presence (of consumers) at the table, followed by subthemes on barriers (tokenism, undermined potential) and surmounting them through reworking power (critical mass and openness to power dynamics). Overall it was found that while there continue to be significant power-related barriers to further building of robust collaborative research with consumers in mental health, there are several avenues that should be considered, much more assertively, to disrupt and transcend them.

What Do Final Year Medical Students Understand by the Concept of Recovery? A Descriptive Qualitative Study.

OBJECTIVE: Traditional teaching in psychiatry does little to address recovery concepts. The aim of this study was to evaluate the incorporation of a recovery-focused teaching program for medical students in psychiatry. METHODS: Recovery, as understood by medical students who had participated in a recovery-focused teaching program, was assessed by thematic analysis of recovery-focused assessment reflections. RESULTS: Six major themes emerged from the recovery reflections from final year medical students are as follows: (1) recovery as a person-centered approach, (2) the need for social integration, (3) non-diagnostic framing of mental illness, (4) tensions between the medical model and personal recovery, (5) a patient's willingness to engage with mental health services, and (6) the development of a positive sense of self. CONCLUSIONS: A recovery teaching program was associated with students expressing knowledge of recovery principles and positive attitudes towards people with experience of mental illness. Psychiatric placements for medical students may benefit from a recovery focus.

Discovering stigma through recovery teaching.

OBJECTIVE: From the perspective of the tutor, course coordinators and a clinical supervisor, we describe and reflect on our observations of innovative service-user led tutorials on recovery that were delivered to final year medical students as part of their psychiatric module. CONCLUSIONS: Much to our surprise, and in contrast to observations elsewhere during the module, students openly expressed blatant stigmatising attitudes in the tutorials on recovery, particularly after spending time with inpatient services. More specifically, they were pessimistic about the possibility of recovery and they struggled to accept the service user status of the recovery tutor. This prompted us to reflect on what and how we teach psychiatry.

Core dimensions of recovery: a psychometric analysis.

Core recovery dimensions lie between the large general factor of recovery and its underlying components. Identifying these could enhance recovery frameworks, practice and research. In contrast to existing conceptually based taxonomies, we sought to empirically identify the core dimensions of recovery through further psychometric analysis of a robust eleven factor (sub-scale) consumer recovery outcome measure, My Voice, My Life. We subjected the sub-scale scores of 504 consumers to further principal components analyses, beginning with a single unrotated factor and progressing through two to nine factors with varimax rotation. We found the five-factor solution to provide an orderly intermediate configuration with the eleven recovery factors having either aligned and/or disengaged through the process to result in the following core dimensions: (1) Belonging and relating (encompassing the individual factors of spirituality, culture, and relationships); (2) Being and doing (encompassing the individual factors of physical health, day-to-day life, and quality of life); (3) Thinking and feeling (encompassing the individual factors of recovery, mental health, and hope and empowerment); (4) Resources (which maintained its independence); and (5) Satisfaction with Services (which also maintained its independence). We compare this empirical configuration with conceptually based taxonomies.

Capacity of forensic patients to consent to treatment.

OBJECTIVE: Lack of capacity to consent to psychiatric treatment has been promoted as a better basis for compulsion than mental disorder plus risk of harm. Previous research has examined how that legal change would affect acutely unwell inpatients. There is little research on forensic patients. This research aimed to assess capacity to consent in forensic patients at different stages of recovery and to consider the implications of respecting their competent treatment decisions. METHOD: Capacity to consent was assessed in a cross-sectional sample of 109 forensic patients both in hospital and in community settings. RESULTS: The majority of participants (67.6%) had treatment-related decision-making capacity. Very few patients with capacity refused treatment. CONCLUSIONS: Change to a capacity-based legal approach may alter treatment for some forensic patients but would not necessarily increase risk of harm to others. The implications for release decisions are less clear.

Development of a self-assessed consumer recovery outcome measure: my voice, my life.

We report the development of a self-assessed consumer recovery outcome measure by way of a consumer led and focused iterative process, informed by exploratory and confirmatory factor analysis. The process began with a deliberately over-inclusive preliminary measure of 127 items, based on 12 presumptive domains derived from the recovery literature and consumer consultation, being piloted with over 500 mental health consumers. The full 504 participant data set was randomly split into two discrete sets of 300 and 204 to provide one for the initial exploratory factor analysis and another (of independence) for the subsequent confirmatory factor analysis and reliability estimation. Analyses identified and confirmed (using the separate data sets) a robust factor structure, with 11 distinct and relatively independent factors (relationships; day-to-day life; culture; physical health; quality of life; mental health; recovery; hope and empowerment; spirituality; resources; and satisfaction with services) underlying one substantial principal construct (that we refer to as consumer recovery). The measure was refined to 65 items, between three and ten items for each of the 11 domains, the reliabilities for which are uniformly high.

A population study of childhood maltreatment and asthma diagnosis: differential associations between child protection database versus retrospective self-reported data.

OBJECTIVE: Despite growing evidence from longitudinal studies of a link between early-life stress and the development of asthma, very few of these examine one of the most severe types of early-life stress: childhood maltreatment. Cross-sectional studies on this topic have relied on retrospective self-reports of maltreatment. This study investigates associations between childhood maltreatment indicated by child protection agency records versus self-reports and lifetime asthma diagnosis in young adults, adjusting for socioeconomic status and mental disorders. METHODS: A nationally representative general population survey of DSM-IV mental disorders in New Zealand (n = 12,992) obtained information on lifetime diagnoses of chronic physical conditions. Information from a subsample of survey respondents aged 16 to 27 years (n = 1413) was linked with a national child protection database to identify respondents with a history of agency involvement, which was used as a proxy for childhood maltreatment. Retrospective reports of maltreatment were also obtained. RESULTS: Child protection agency history was associated with elevated odds (odds ratio = 2.88 [95% confidence interval = 1.7-4.74]) of a lifetime diagnosis of asthma. After adjusting for a variety of indicators of socioeconomic status, lifetime mental disorders, lifetime smoking, and body mass index, this association remained significantly elevated (odds ratio = 2.26 [95% confidence interval = 1.33-3.83]). Retrospectively self-reported maltreatment in childhood was not associated with asthma. CONCLUSIONS: Childhood maltreatment was associated with elevated odds of asthma diagnosis. These findings are consistent with the possibility that early-life stress may be one of the environmental factors that increase the risk of asthma in genetically vulnerable individuals.

Childhood maltreatment and DSM-IV adult mental disorders: comparison of prospective and retrospective findings.

BACKGROUND: Prior research reports stronger associations between childhood maltreatment and adult psychopathology when maltreatment is assessed retrospectively compared with prospectively, casting doubt on the mental health risk conferred by maltreatment and on the validity of retrospective reports. AIMS: To investigate associations of psychopathology with prospective v. retrospective maltreatment ascertainment. METHOD: A nationally representative sample of respondents aged 16-27 years (n = 1413) in New Zealand completed a retrospective assessment of maltreatment and DSM-IV mental disorders. Survey data were linked with a national child protection database to identify respondents with maltreatment records (prospective ascertainment). RESULTS: Childhood maltreatment was associated with elevated odds of mood, anxiety and drug disorders (odds ratios = 2.1-4.1), with no difference in association strength between prospective and retrospective groups. Prospectively ascertained maltreatment predicted unfavourable depression course involving early onset, chronicity and impairment. CONCLUSIONS: Prospectively and retrospectively assessed maltreatment elevated the risk of psychopathology to a similar degree. Prospectively ascertained maltreatment predicted a more unfavourable depression course.

Learning is what happens between seeing patients: defining clinical access.

The inability to access clinical placements during the COVID-19 pandemic stimulated us to reflect on key elements of the experience, beyond history taking and examination. We were also mindful of concerns about work readiness of new graduates. We identified seven aspects of clinical experience distinct from those requiring direct patient contact. These are: recognise and contribute to the collective competence of multidisciplinary teams; apply project management principles to the complexities of clinical care; integrate personal and team-based clinical reasoning; deliver patient-centred collaborative care; achieve an integrated perspective of clinical care; demonstrate adaptability to health systems; consolidate professional identity formation. We consider that making these aspects explicit in learning objectives and assessments in medical schools is likely to improve the work-readiness of new graduates and should also be reflected in accreditation standards.

Changes in the development of opioid tolerance on re-exposure among people who use heroin: A qualitative study.

BACKGROUND AND AIMS: This qualitative study aimed to explore how the development of tolerance to both the psychoactive and respiratory depressant effects of heroin on re-exposure are experienced by people who use heroin. METHODS: Semi-structured one-to-one interviews were conducted with 20 adults who currently or previously used heroin (for at least 6 months), with any type of administration (injected, smoked) and experience of abstinence (at least 2 weeks) and relapse. Topic guides explored the participants understanding of tolerance, their experience of developing tolerance to heroin and of tolerance following relapse. Interviews were audio-recorded and transcribed. Thematic analysis was used to generate salient themes. RESULTS: The analysis produced three broad themes: lay understanding of tolerance; tolerating tolerance; and rapid tolerance development following relapse. Tolerance was defined as the body adapting to regular drug use, so that the drug no longer produced the same level of effect. Tolerance was experienced as interacting and co-developing with physical dependence and the symptoms of withdrawal. Indeed, several participants did not differentiate between tolerance and dependence. Most participants did not notice tolerance to respiratory depression. Tolerance levels fluctuated-increasing over periods of regular use and reducing when abstinent. Using more drug was the most common response to increasing tolerance to the desired effects. On re-use following abstinence, tolerance was experienced as developing more quickly in the most recent relapse compared to the first. Tolerance was also perceived to return more quickly with each abstinence-relapse cycle. CONCLUSIONS: Qualitative accounts of tolerance report that tolerance returns more quickly with each relapse episode. By elucidating the mechanism(s) involved and potentially discovering how they could be switched on prior to relapse occurring we might be able to develop a beneficial harm reduction treatment for people in abstinence that would protect against overdose occurring on subsequent relapse.

The low pass rate in the RANZCP clinical examinations: is the exam the problem?

OBJECTIVES: The aim of this study was to examine the role of supervision during psychiatric training in ensuring that registrars are adequately trained to meet the standards of the RANZCP examinations and to consider the implications for improving examination pass rates. METHOD: Audiotaped recordings of 50 h of supervision involving six supervisors and thirteen trainees, obtained 2000-2003, were transcribed and analysed thematically in a qualitative study, informed by a postmodern, foucaultian perspective. RESULTS: Until an examination loomed, supervisors rarely required evidence of theoretical study or structured case presentations from their trainees. The examination and the examiners served to justify the supervisors requiring such discipline. This enabled the supervisors to remain in a supportive role, while requiring higher standards from trainees. Paradoxically, while requiring higher standards 'for the exam', trainees were told that the examiners expected nothing more than 'good psychiatric practice'. In presenting cases, the attributes of prioritization, thoughtfulness, conciseness and good timing were valued, as reported in both undergraduate and other postgraduate medical training. CONCLUSIONS: Much of supervision bore little relationship to preparation for college examinations until these were imminent. While the daily practice of trainees and supervisors continues to be at variance with the practices required to pass the examination (reflected by reference to 'exam-style' and 'non-exam style' presentations) the pass rates will remain low. If we believe that the standard set in the examination is that required of a practising psychiatrist, change is required to supervision and daily practice standards to reflect these standards.

Establishing an expert mental health consumer research group: Perspectives of nonconsumer researchers.

PURPOSE: To explore the views and opinions of nonconsumer researchers to the concept of an Expert Consumer Researcher Group. DESIGN AND METHODS: Qualitative exploratory involving individual interviews with nonconsumer mental health researchers experienced in working collaboratively with consumer researchers. Data were analyzed thematically. FINDINGS: Participants viewed the concept positively, albeit with caution. Perceived advantages included: greater visibility and enhanced access; collegiality; sharing and creating expertise; broader acceptance; making it mandatory; and structure and location. Participants were concerned about potential tokenism and implementation barriers. PRACTICE IMPLICATIONS: Consumer involvement enhances the quality and relevance of research, potentially impacting clinical practice.