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The nematode Caenorhabditis elegans contains genes for two types of ferritin (ftn-1 and ftn-2) that express FTN-1 and FTN-2. We have expressed and purified both proteins and characterized them by X-ray crystallography, cryo-electron microscopy, transmission electron microscopy, dynamic light scattering, and kinetically by oxygen electrode and UV-vis spectroscopy. Both show ferroxidase activity, but although they have identical ferroxidase active sites, FTN-2 is shown to react approximately 10 times faster than FTN-1, with L-type ferritin character over longer time periods. We hypothesize that the large variation in rate may be due to differences in the three- and four-fold channels into the interior of the protein 24-mer. FTN-2 is shown to have a wider entrance into the three-fold channel than FTN-1. Additionally, the charge gradient through the channel of FTN-2 is more pronounced, with Asn and Gln residues in FTN-1 replaced by Asp and Glu residues in FTN-2. Both FTN-1 and FTN-2 have an Asn residue near the ferroxidase active site that is a Val in most other species, including human H ferritin. This Asn residue has been observed before in ferritin from the marine pennate diatom Pseudo-mitzchia multiseries. By replacing this Asn residue with a Val in FTN-2, we show that the reactivity decreases over long time scales. We therefore propose that Asn106 is involved in iron transport from the ferroxidase active site to the central cavity of the protein.

Chaperones and other quality control machinery guard proteins from inappropriate aggregation, which is a hallmark of neurodegenerative diseases. However, how the systems that regulate the "foldedness" of the proteome remain buffered under stress conditions and in different cellular compartments remains incompletely understood. In this study, we applied a FRET-based strategy to explore how well quality control machinery protects against the misfolding and aggregation of "bait" biosensor proteins, made from the prokaryotic ribonuclease barnase, in the nucleus and cytosol of human embryonic kidney 293T cells. We found that those barnase biosensors were prone to misfolding, were less engaged by quality control machinery, and more prone to inappropriate aggregation in the nucleus as compared with the cytosol, and that these effects could be regulated by chaperone Hsp70-related machinery. Furthermore, aggregation of mutant huntingtin exon 1 protein (Httex1) in the cytosol appeared to outcompete and thus prevented the engagement of quality control machinery with the biosensor in the cytosol. This effect correlated with reduced levels of DNAJB1 and HSPA1A chaperones in the cell outside those sequestered to the aggregates, particularly in the nucleus. Unexpectedly, we found Httex1 aggregation also increased the apparent engagement of the barnase biosensor with quality control machinery in the nucleus suggesting an independent implementation of "holdase" activity of chaperones other than DNAJB1 and HSPA1A. Collectively, these results suggest that proteostasis stress can trigger a rebalancing of chaperone abundance in different subcellular compartments through a dynamic network involving different chaperone-client interactions.

Contains fulltext : 235318.pdf (Publisher’s version ) (Open Access), BACKGROUND AND PURPOSE: For irradiation of localized prostate-cancer, moderately-hypofractionated regimens with a variety of dose per fraction are used. We adopted a regimen of 70 Gy in 28 fractions of 2.5 Gy, using state of the art radiotherapy (RT) and closely monitored the efficacy, toxicity and health-related quality of life (HRQoL) in a large cohort, using patient-reported outcomes. MATERIALS AND METHODS: Between 2008 and 2016, 462 patients with intermediate- to high-risk localized prostate cancer were treated with RT, 28 fractions of 2.5 Gy, using IMRT/VMAT, an online fiducial-maker based correction protocol and a daily inserted endorectal balloon. Overall freedom from failure (no biochemical or clinical recurrence) , as well as self-reported genitourinary (GU) and gastrointestinal (GI) related toxicity and HRQoL are reported. RESULTS: Overall freedom from failure rates at 3 and 5 years were 92.0% (89.1-94.9%) and 83.5% (78.6-88.4%), respectively. Prevalence rates of grade ≥ 2 GU/GI-toxicity were 16.3%/6.3% and 22,1%/3.2% after 3 and 5 years respectively. The 5-year actuarial incidences of grade ≥ 2 GU/GI-toxicity were 43.5%/18.5%. HRQoL worsened during RT and gradually recovered thereafter, In accordance with the prevalence rates. CONCLUSION: Treatment of intermediate- or high-risk localized prostate cancer with RT to 70 Gy in 28 fractions with IMRT/VMAT, using fiducial markers and an endorectal balloon leads to good long-term tumor control rates and acceptable patient reported toxicity rates. Furthermore, patient-reported outcomes, including HRQoL, are essential for a good comparison between different studies. Finally, prevalence rates show a better correlation with HRQoL than actuarial incidence rates do and might therefore better represent the burden of toxicity.

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

CONTEXT: When errors occur in clinical settings, it is important that they are recognised without defensiveness so that prompt corrective action can be taken and learning can occur. Cognitive dissonance - the uncomfortable tension we experience when we hold two or more inconsistent beliefs - can hinder our ability to respond optimally to error. OBJECTIVES: The aim of this paper is to describe the effects of cognitive dissonance, a construct developed and tested in social psychology. We discuss the circumstances under which dissonance is most likely to occur, provide examples of how it may influence clinical practice, discuss potential remedies and suggest future research to test these remedies in the clinical context. METHODS: We apply research on cognitive dissonance from social psychology to clinical settings. We examine the factors that make dissonance most likely to occur. We illustrate the power of cognitive dissonance through two medical examples: one from history and one that is ongoing. Finally, we explore moderators at various stages of the dissonance process to identify potential remedies. RESULTS: We show that there is great opportunity for cognitive dissonance to distort judgements, delay optimal responses and hinder learning in clinical settings. We present a model of the phases of cognitive dissonance, and suggestions for preventing dissonance, reducing the distortions that can arise from dissonance and inhibiting dissonance-induced escalation of commitment. CONCLUSIONS: Cognitive dissonance has been studied for decades in social psychology but has not had much influence on medical education research. We argue that the construct of cognitive dissonance is very relevant to the clinical context and to medical education. Dissonance has the potential to interfere with learning, to hinder the process of coping effectively with error, and to make the accepting of change difficult. Fortunately, there is the potential to reduce the negative impact of cognitive

There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer's disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer's disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients' rights and well-being are protected when such therapeutic options become available.

Item does not contain fulltext, OBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of approximately 30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of euro7,133 (95% confidence interval [95% CI] euro6,071, euro8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was euro368,269 (95% CI euro155,132, euro1,675,909) and euro17,670 (95% CI euro13,650, euro22,721), respectively. At a WTA of euro98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of euro368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay.

OBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of ∼30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of €7,133 (95% confidence interval [95% CI] €6,071, €8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was €368,269 (95% CI €155,132, €1,675,909) and €17,670 (95% CI €13,650, €22,721), respectively. At a WTA of €98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of €368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay.

BACKGROUND: Reflection on learning is an essential component of effective learning. Deconstructing the components of reflection on learning using a self-regulated learning (SRL) framework, allows the assessment of students' ability to reflect on their learning. The aim of this study was to validate an instrument to measure medical students' reflection on their learning. METHODS: A systematic search was conducted to identify the most suitable instrument to measure students' reflection on their learning based on the theoretical framework of SRL. The search identified the Motivated Strategies for Learning Questionnaire (MSLQ) which contained five subscales: internal goal orientation, self-efficacy, critical thinking, metacognitive/self-regulation, help seeking and peer learning. Using the original MSLQ as the foundation, we carried out three phases of a research program to develop a useful set of items: an expert panel's review of items, a substantial pilot study, and a factor analysis of ratings of a modified set of items by preclinical and final year medical students. RESULTS: The factor analysis of the Modified MSLQ extracted four subscales with reasonable internal consistency: self-orientation, critical thinking, self-regulation and feedback-seeking. Each subscale correlates highly with the Modified MSLQ score, with modest inter-correlations between the subscales suggesting that they are measuring different components of the total score. CONCLUSION: Medical students and their educators need to be able to monitor their learning in their complex academic and clinical environments. The Modified MSLQ provides a means of investigating and tracking individual medical students' reflections on their learning.

Background: Despite the growing use, studies have demonstrated some limitations related to the feedback provided in the context of the increasing use of the Mini Clinical Evaluation Exercise (Mini-CEX) in undergraduate medical education. This study examined the written feedback provided on the Mini-CEX form to determine its usefulness as a learning tool for students.Methods: 1427 Mini-CEX assessment forms of final year medical students were collected. Written feedback, both on students' strength and weakness, was categorized and correlated with the variables of clinical case complexity, assessors' clinical position and students' clinical performance rating. Results: The number of general feedback comments for students' strengths and development were 953 (65.3%) and 604 (38.64%) respectively. Less than 30% of the feedback for each domain was categorized as specific feedback. Significant associations were found between feedback on strength and clinical case complexity (Chi2=17.48, p <.01); and also with assessor clinical position (Chi2=37.10, p <.01). There was also an association between feedback for students' development and assessor clinical position (Chi2=27.22, p <.01).Conclusion: Based on the Mini-CEX forms of student cohort this study examined, it can be concluded that the written feedback provided in the Mini-CEX assessment form was general and lacked specificity. This finding leads to the need to train clinical teachers in the provision of feedback., Hintergrund: Trotz steigender Anwendungszahlen der Mini Clinical Evaluation Exercise (Mini-CEX) Prüfung, die in der medizinischen Grundausbildung zunehmend genutzt wird, haben Studien einige Einschränkungen im Zusammenhang mit dem abgegebenen Feedback (Rückmeldung) gezeigt.Diese Studie überprüft das schriftlich abgegebene Feedback auf Mini-CEX-Formularen, um die Nutzbarkeit dieser als Lernhilfsmittel für Studenten zu bestimmen.Methoden: 1427 Mini-CEX-Bewertungsformulare wurden von Medizinstudenten aus deren letztem Studienjahr gesammelt. Das schriftliche Feedback, das sich auf Stärken und Schwächen der Studierenden bezieht, wurde kategorisiert und mit den Variablen der Komplexität der klinischen Fälle, der klinischen Position der Gutachter und der klinischen Leistungsbewertung der Studierenden korreliert.Ergebnisse: Die Anzahl der allgemeinen Feedback-Kommentare bezüglich der Stärken und der Weiterentwicklung der Studenten betrug 953 (65,3%) bzw. 604 (38,64%). Weniger als 30% der Rückmeldungen zu jeder Domäne wurde als spezifisches Feedback kategorisiert. Signifikante Zusammenhänge wurden zwischen dem Feedback zu den Stärken eines Studenten und der Komplexität der klinischen Fälle (Chi2=17,48, p <0,01) sowie der klinischen Position der Gutachter (Chi2=37,10, p <.01) gefunden. Ebenfalls bestand ein Zusammenhang zwischen dem Feedback zur Weiterentwicklung der Studierenden und der klinischen Position der Gutachter (Chi2=27,22, p <0,01).Schlussfolgerung: Basierend auf den Mini-CEX-Formularen der Studentengruppe, die in dieser Studie untersucht wurde, kann man schließen, dass das in den Mini-CEX Bewertungsformularen abgegebene schriftliche Feedback allgemeiner Natur und wenig spezifisch war. Dieser Befund zeigt auf, dass klinische Lehrer besser für die Bereitstellung von Feedback ausgebildet werden müssen.

Professional identity formation is acknowledged as one of the fundamental tasks of contemporary medical education. Identity is a social phenomenon, constructed through participation in everyday activities and an integral part of every learning interaction. In this paper we report from an Australian ethnographic study into how medical students and patients use narrative to construct their identities. The dialogic narrative analysis employed focused on the production of meaning through the use of language devices in a given context, and the juxtaposition of multiple perspectives. Two stories told by students about their participation in patient care-related activities reveal how identities are constructed in this context through depictions of the relationships between medical students, patients and clinical teachers. These students use the rhetorical functions of stories to characterise doctors and patients in certain ways, and position themselves in relation to them. They defend common practices that circumvent valid consent processes, justified by the imperative to maximise students' participation in patient care-related activities. In doing so, they identify patients as their adversaries, and doctors as allies. Both students are influenced by others' expectations but one reveals the active nature of identity work, describing subtle acts of resistance. These stories illustrate how practices for securing students' access to patients can influence students' emerging identities, with implications for their future disclosure and consent practices. We argue that more collaborative ways of involving medical students in patient care-related activities will be facilitated if students and clinical teachers develop insight into the relational nature of identity work.

CONTEXT: The black box that is student learning in clinical environments is an ongoing research project. Our previous research showed that despite the time that students are given to learn with, about and from patients, some lack confidence for those encounters and see few patients. The study reported here investigated individual and environmental factors affecting medical students' self-directed learning time in hospital. METHODS: We studied second year students in the four-year postgraduate Melbourne Medical School programme as they undertook the first of their four 9-week hospital placements in medical wards. Each week approximately 10 hours of structured teaching is offered; the remaining time is spent in self-directed learning. Over six weeks, we observed 31 medical students and interviewed 17 of them. The interviews were subjected to content analysis procedures and the observation notes added contextual information to what was said in interviews. We considered the findings through the Experience-based Learning framework. RESULTS: We found four main themes in the data: finding and contacting patients challenges all students and overwhelms some; the educational design of the placement is a flawed navigational device providing inadequate clarity and security; the physical and social terrain of a large tertiary hospital is replete with obstacles making it easy for some students to stumble and retreat; finally, any positive connection with peers, staff and patients is empowering. CONCLUSIONS: This study throws light on to the uncertain path of the novice clinical learner illuminating both the intractable aspects of hospital environments and opportunities for pedagogical and affective supports that can compensate. The processes and conditions for self-directed learning time need attention in order to provide for a safe, efficient or successful clerkship experience for all students. Particular effort is needed to sensitively identify those individuals who struggle an

Large-scale interview and simulation-based assessments such as objective structured clinical examinations (OSCEs) and multiple mini interviews (MMIs) are logistically complex to administer, generate large volumes of assessment data, and are strong candidates for the adoption of computer-based marking systems. Adoption of new technologies can be challenging, and technical failures, which are relatively commonplace, can delay and/or create resistance to ongoing implementation.This paper reports on the adoption process of an electronic marking system for OSCEs and MMIs following an unsuccessful initial trial. It describes how, after the initial setback, a staged implementation, progressing from small to larger-scale assessments, single to multiple assessment types, and lower to higher stakes assessments, was used to successfully adopt and embed iPad-based marking within our medical school.Critical factors in the success of this approach included thorough appraisal and selection of technologies, rigorous assurance of system reliability and security, constant review and refinement, and careful attention to implementation and end-user training. Engagement of stakeholders is also crucial, especially in the case of previous failures or setbacks. The early identification and recruitment of staff to provide specific expertise and support for adoption of an innovation helps to facilitate this process with four key roles proposed; those of innovation advocate, champion, expert and sponsor.

BACKGROUND: The majority of schools in the Asia-Pacific region have adopted medical curricula based on western pedagogy. However to date there has been minimal exploration of the influence of the culture of learning on the teaching and learning process. This paper explores this issue in relation to clinical reasoning. METHOD: A comparative case study was conducted in 2 medical schools in Australia (University of Melbourne) and Asia (Universitas Indonesia). It involved assessment of medical students' attitudes to clinical reasoning through administration of the Diagnostic Thinking Inventory (DTI), followed by qualitative interviews which explored related cultural issues. A total of 11 student focus group discussions (45 students) and 24 individual medical teacher interviews were conducted, followed by thematic analysis. RESULTS: Students from Universitas Indonesia were found to score lower on the Flexibility in Thinking subscale of the DTI. Qualitative data analysis based on Hofstede's theoretical constructs concerning the culture of learning also highlighted clear differences in relation to attitudes to authority and uncertainty avoidance, with potential impacts on attitudes to teaching and learning of clinical reasoning in undergraduate medical education. CONCLUSIONS: Different attitudes to teaching and learning clinical reasoning reflecting western and Asian cultures of learning were identified in this study. The potential impact of cultural differences should be understood when planning how clinical reasoning can be best taught and learned in the changing global contexts of medical education, especially when the western medical education approach is implemented in Asian contexts.