Guest Editors' Introduction

‘I shall have to speak of things, of which I cannot speak’, writes Samuel Beckett in The Unnameable, ‘but also, which is even more interesting, but also that I, which is if possible even more interesting, that I shall have to, I forget, no matter’. Listening to the voice of folly can be like this: an endless flow of inconsistencies, of contradictions, sayings and unsayings; a tantalising, mischievous mockery of speech –unable to go on, unable to end. And yet – as this volume shows – we are irresistibly drawn to folly, its promises, its whispers of ‘even more interesting’ things: of how we are split between conscious and unconscious, familiar and unfamiliar, same and other. For psychoanalysis, folly is not only a site of hidden truths; it is also, perhaps more importantly, a source of unconscious freedom, a momentary escape from our obsession with rules and order. According to Christopher Bollas, the unconscious self is like a fool, who ‘raises potentially endless questions about diverse and disparate issues’ and thereby provides us with a ‘separate sense’, which opens us to others and to our own creative potential. As Rachel Bowlby elegantly puts it, folly is a ‘soul-mole’, forever shovelling our secrets out into the light: ‘there’s no possible moment of release or resignation when the mole might stop vainly, interminably working away’. Folly’s subversive, creative soliloquies reveal to us a psychic ‘underground repertoire of secrets’; they challenge our established knowledge and invite us, as Bolwby shows, to endless, titillating games of ‘suppression and confession’. For Anne Duprat, this deep-seated playfulness explains folly’s close relation to fiction: what makes them so atone is their ‘capacity of creating alternative representations of the world — and thus of re-figuring the world depicted by reason or history – […] but also their paradoxical structure, and hence the instability of their speech acts, which deny, suspend, or do not seriously guarantee the truth of their statements’. (First paragraph

Population history from the Neolithic to present on the Mediterranean island of Sardinia: an ancient DNA perspective

Recent ancient DNA studies of western Eurasia have revealed a dynamic history of admixture, with evidence for major migrations during the Neolithic and Bronze Age. The population of the Mediterranean island of Sardinia has been notable in these studies –} Neolithic individuals from mainland Europe cluster more closely with Sardinian individuals than with all other present-day Europeans. The current model to explain this result is that Sardinia received an initial influx of Neolithic ancestry and then remained relatively isolated from expansions in the later Neolithic and Bronze Age that took place in continental Europe. To test this model, we generated genome-wide capture data (approximately 1.2 million variants) for 43 ancient Sardinian individuals spanning the Neolithic through the Bronze Age, including individuals from Sardinia{’}s Nuragic culture, which is known for the construction of numerous large stone towers throughout the island. We analyze these new samples in the context of previously generated genome-wide ancient DNA data from 972 ancient individuals across western Eurasia and whole-genome sequence data from approximately 1,500 modern individuals from Sardinia. The ancient Sardinian individuals show a strong affinity to western Mediterranean Neolithic populations and we infer a high degree of genetic continuity on the island from the Neolithic (around fifth millennium BCE) through the Nuragic period (second millennium BCE). In particular, during the Bronze Age in Sardinia, we do not find significant levels of the {“}Steppe{” ancestry that was spreading in many other parts of Europe at that time. We also characterize subsequent genetic influx between the Nuragic period and the present. We detect novel, modest signals of admixture between 1,000 BCE and present-day, from ancestry sources in the eastern and northern Mediterranean. Within Sardinia, we confirm that populations from the more geographically isolated mountainous provinces have experienced elevated levels of genetic drift and that northern and southwestern regions of the island received more gene flow from outside Sardinia. Overall, our genetic analysis sheds new light on the origin of Neolithic settlement on Sardinia, reinforces models of genetic continuity on the island, and provides enhanced power to detect post-Bronze-Age gene flow. Together, these findings offer a refined demographic model for future medical genetic studies in Sardinia

Psychological morbidity and health related quality of life after injury: multicentre cohort study

Purpose To demonstrate the impact of psychological morbidity 1 month post-injury on subsequent post-injury quality of life (HRQoL) in a general injury population in the UK to inform development of trauma care and rehabilitation services. Methods Multicentre cohort study of 16–70-year-olds admitted to 4 UK hospitals following injury. Psychological morbidity and HRQoL (EQ-5D-3L) were measured at recruitment and 1, 2, 4 and 12 months post-injury. A reduction in EQ-5D compared to retrospectively assessed pre-injury levels of at least 0.074 was taken as the minimal important difference (MID). Multilevel logistic regression explored relationships between psychological morbidity 1 month post-injury and MID in HRQoL over the 12 months after injury. Results A total of 668 adults participated. Follow-up rates were 77% (1 month) and 63% (12 months). Substantial reductions in HRQoL were seen; 93% reported a MID at 1 month and 58% at 12 months. Problems with pain, mobility and usual activities were commonly reported at each time point. Depression and anxiety scores 1 month post-injury were independently associated with subsequent MID in HRQoL. The relationship between depression and HRQoL was partly explained by anxiety and to a lesser extent by pain and social functioning. The relationship between anxiety and HRQoL was not explained by factors measured in our study. Conclusions Hospitalised injuries result in substantial reductions in HRQoL up to 12 months later. Depression and anxiety early in the recovery period are independently associated with lower HRQoL. Identifying and managing these problems, ensuring adequate pain control and facilitating social functioning are key elements in improving HRQoL post-injury

Exploring High Aspect Ratio Gold Nanotubes as Cytosolic Agents: Structural Engineering and Uptake into Mesothelioma Cells.

The generation of effective and safe nanoagents for biological applications requires their physicochemical characteristics to be tunable, and their cellular interactions to be well characterized. Here, the controlled synthesis is developed for preparing high-aspect ratio gold nanotubes (AuNTs) with tailorable wall thickness, microstructure, composition, and optical characteristics. The modulation of optical properties generates AuNTs with strong near infrared absorption. Surface modification enhances dispersibility of AuNTs in aqueous media and results in low cytotoxicity. The uptake and trafficking of these AuNTs by primary mesothelioma cells demonstrate their accumulation in a perinuclear distribution where they are confined initially in membrane-bound vesicles from which they ultimately escape to the cytosol. This represents the first study of the cellular interactions of high-aspect ratio 1D metal nanomaterials and will facilitate the rational design of plasmonic nanoconstructs as cytosolic nanoagents for potential diagnosis and therapeutic applications.BLF-Papworth Fellowship from the British Lung Foundation and the Victor Dahdaleh Foundation

Psychological morbidity and return to work after injury: multicentre cohort study

Background: The benefits of work for physical, psychological and financial wellbeing are well documented. Return to work (RTW) after unintentional injury is often delayed, and psychological morbidity may contribute to this delay. The impact of psychological morbidity on RTW after a wide range of unintentional injuries in the UK has not been adequately quantified. Aims: To quantify the role of psychological factors including anxiety, depression and post-traumatic distress on RTW following unintentional injuries. Design and Setting: Longitudinal multi-centre prospective study in Nottingham, Bristol, Leicester and Guildford, UK Method: Participants (n=273) were 16-69 year olds admitted to hospital following unintentional injury and, in paid employment prior to injury. They were surveyed at baseline, 1, 2, 4 and 12 months following injury on demographic and injury characteristics, psychological morbidity and RTW status. Associations between demographic, injury and psychological factors and RTW status were quantified using random effects logistic regression. Results: The odds of RTW reduced as depression scores one month post-injury increased (OR 0.87, 95%CI 0.79, 0.95) and as length of hospital stay increased (OR 0.91, 95%CI 0.86, 0.96). Those experiencing threatening life events following injury (OR 0.27, 95%CI 0.10, 0.72) and with higher scores on the crisis social support scale (OR 0.93, 95%CI 0.88, 0.99) had a lower odds of RTW. Multiple imputation analysis found similar results except crisis social support did not remain significant. Conclusion: Primary care professionals can identify patients at risk of delayed RTW who may benefit from management of psychological morbidity and support to RTW

Characteristics of Global Health Careers among Graduates of a Global Health Equity Residency Training Program in the United States

Background: The number of global health (GH) physician training programs in the United States has increased in the past decade. Few studies have explored the demographics of individuals in these programs, the impact of global health training on career development, and specific factors associated with whether graduates achieve a career in global health. Objectives: We aimed to describe characteristics of program graduates and quantify which previously identified factors were associated with achieving a self-defined career in GH among a cohort of graduates from one GH post-graduate training program in a highly resourced academic medical center in the United States between 2003 and 2018. Methods: We conducted a cross-sectional survey and analyzed differences between participants who self-identified as having a career in GH compared to those who did not. Findings: Among 59 individuals invited to participate, 53 (89.9%) responded to the survey. Having a GH mentor was associated with having a career in GH (OR 10.3; p = 0.004). Those who had a GH career were more likely to have a clearly-defined career path (p = 0.03), have institutional support in their current job (p = 0.00006), be able to manage the split between their GH and non-GH work (p = 0.0001), find funding to achieve their objectives in GH (p = 0.01), invest in their personal and family life (p = 0.05), and split work abroad and domestically with few challenges (p = 0.01). Conclusions: We present sociodemographic and career characteristics for graduates from a GH training program in a highly resourced academic medical center in the United States. Mentorship, institutional support, funding, ability to balance GH with non-GH work, and time spent domestically or abroad are key factors associated with successful careers in GH. If institutional funding is allocated to strengthen these aspects of GH training, we anticipate more sustained GH career development

Mental health and other factors associated with work productivity post injury in the UK: multicentre cohort study

Introduction: Mental health conditions are a major contributor to productivity loss and are common post-injury. This study quantifies post-injury productivity loss and its association with pre and post-injury mental health, injury, demographic, health, social and other factors. Methods: Multi-centre, longitudinal study recruiting hospitalised 16-69-year-old employed individuals with unintentional injuries, followed-up at 1,2,4 and 12 months. Participants completed questionnaires on injury, demographic factors, health (including mental health), social factors, other factors and on-the-job productivity upon return to work (RTW). Odds ratios were estimated for above median productivity loss, using random effects logistic regression. Results: 217 adults had made a RTW at 2,4 or 12-months post-injury: 29% at 2-months, 66% at 4-months, and 83% at 12-months. Productivity loss reduced over time: 3.3% of working time at 2-months, 1.7% at 4-months, 1% at 12-months. Significantly higher productivity loss was associated with pre-injury psychiatric conditions (OR 21.40, 95% CI: 3.50, 130.78) and posttraumatic stress avoidance symptoms at 1-month (OR for one-unit increase in score 1.15, 95%CI 1.07, 1.22). Significantly lower productivity loss was associated with male gender (OR 0.32, 95%CI 0.14, 0.74), upper and lower limb injuries (vs other body regions, OR 0.15, 95% CI: 0.03, 0.81), and sports injuries (vs. home, OR 0.18, 95% CI: 0.04, 0.78). Pre-injury psychiatric conditions and gender remained significant in analysis of multiply imputed data. Conclusions: Unintentional injury results in substantial productivity loss. Those with pre-injury psychiatric conditions, females and posttraumatic stress avoidance symptoms experience greater productivity loss and may require additional support to successfully RTW

First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Psychological morbidity and return to work after injury: multicentre cohort study

Background: The benefits of work for physical, psychological and financial wellbeing are well documented. Return to work (RTW) after unintentional injury is often delayed, and psychological morbidity may contribute to this delay. The impact of psychological morbidity on RTW after a wide range of unintentional injuries in the UK has not been adequately quantified.Aims: To quantify the role of psychological factors including anxiety, depression and post-traumatic distress on RTW following unintentional injuries.Design and Setting: Longitudinal multi-centre prospective study in Nottingham, Bristol, Leicester and Guildford, UKMethod: Participants (n=273) were 16-69 year olds admitted to hospital following unintentional injury and, in paid employment prior to injury. They were surveyed at baseline, 1, 2, 4 and 12 months following injury on demographic and injury characteristics, psychological morbidity and RTW status. Associations between demographic, injury and psychological factors and RTW status were quantified using random effects logistic regression.Results: The odds of RTW reduced as depression scores one month post-injury increased (OR 0.87, 95%CI 0.79, 0.95) and as length of hospital stay increased (OR 0.91, 95%CI 0.86, 0.96). Those experiencing threatening life events following injury (OR 0.27, 95%CI 0.10, 0.72) and with higher scores on the crisis social support scale (OR 0.93, 95%CI 0.88, 0.99) had a lower odds of RTW. Multiple imputation analysis found similar results except crisis social support did not remain significant.Conclusion: Primary care professionals can identify patients at risk of delayed RTW who may benefit from management of psychological morbidity and support to RTW

Psychological morbidity and health related quality of life after injury: multicentre cohort study

Purpose: To demonstrate the impact of psychological morbidity 1 month post-injury on subsequent post-injury quality of life (HRQoL) in a general injury population in the UK to inform development of trauma care and rehabilitation services. Methods: Multicentre cohort study of 16–70-year-olds admitted to 4 UK hospitals following injury. Psychological morbidity and HRQoL (EQ-5D-3L) were measured at recruitment and 1, 2, 4 and 12 months post-injury. A reduction in EQ-5D compared to retrospectively assessed pre-injury levels of at least 0.074 was taken as the minimal important difference (MID). Multilevel logistic regression explored relationships between psychological morbidity 1 month post-injury and MID in HRQoL over the 12 months after injury. Results: A total of 668 adults participated. Follow-up rates were 77% (1 month) and 63% (12 months). Substantial reductions in HRQoL were seen; 93% eported a MID at 1 month and 58% at 12 months. Problems with pain, mobility and usual activities were commonly reported at each time point. Depression and anxiety scores month post-injury were independently associated with subsequent MID in HRQoL. The relationship between depression and HRQoL was partly explained by anxiety and to a lesser extent by pain and social functioning. The relationship between anxiety and HRQoL was not explained by factors measured in our study. Conclusions: Hospitalised injuries result in substantial reductions in HRQoL up to 12 months later. Depression and anxiety early in the recovery period are independently associated with lower HRQoL. Identifying and managing these problems, ensuring adequate pain control and facilitating social functioning are key elements in improving HRQoL post-injury