Background and Purpose Post-stroke morbidity is common, but little is known about the burden on patients’ lives from their own perspective. Understanding morbidity from the point of view of the patient may support targeted intervention in post-stroke recovery. This study used a stroke specific Patient Reported Outcome Measure (PROM) containing Mental health (MH) and Physical Health (PH) domains and 5 stroke specific questions. We aimed to consider trends over a 6-month period and further assess the association between the MH and PH measures and common clinical measures. Methods A multicenter prospective cohort study was conducted at 19 hospital sites across England and Wales. Patients were enrolled from August 2018 to September 2019. Clinical measures and PROMs were assessed at three timepoints: acutely following the index stroke, at 3 and 6-months post-stroke. Clinical measures and PROMs were assessed in each of these points. Results Physical health PROM domains show significant gradual improvement across the study period (χ2 42.6312, p<0.0001), whereas cognitive function domains (χ2 3.7849, p<0.875) did not echo this trend. All clinical measures (GAD-7, PHQ9, MoCA, MRS) were associated with poorer PROM MH outcomes, (aMD -4.4, CI -0.59, -0.29, p≤0.001, aMD -0.45, CI -0.59, -0.32, p= <0.001, aMD 0.75, CI 0.56, 0.95, aMD -1.91, CI -2.41, -1.47, p≤0.001). Clinical measures of disability, as per the MRS, are associated with poor PROM PH scores (aMD -0.57, 95% CI -0.94, -0.20, p=0.003). Conclusions This research indicates there is unmet cognitive burden in stroke survivors. PROMs may be able to measure unmet more discretely than common clinical tools that are used post-stroke. Further research and guidance on how to integrate PROMs into current clinical frameworks is essential.

Between-sex differences in the presentation, risk factors, management, and outcomes of acute myocardial infarction (MI) are well documented. However, as such differences are highly sensitive to cultural and social changes, there is a need to continuously re-evaluate the evidence. The present contemporary systematic review assesses the baseline characteristics of men and women presenting to secondary, tertiary, and quaternary centres with acute myocardial infarction (MI). Over 1.4 million participants from 18 studies, including primary prospective, cross sectional and retrospective observational studies, as well as secondary analysis of registry data are included in the study. The study showed that women were more likely than men to have a previous diagnosis of diabetes, hypertension, cerebrovascular disease, and heart failure. They also had lower odds of presenting with previous ischaemic heart disease and angina, dyslipidaemia, or a smoking history. Further work is necessary to understand the reasons for these differences, and the role that gender-specific risk factors may have in this context. Moreover, how these between-gender differences are implicated in management and outcomes also requires further work.

BACKGROUND:We sought to explore associations between trainee doctor perception and excess patient mortality.METHODS:Data from two publicly available databases reflecting mortality and components of trainee satisfaction within 81 NHS healthcare institutions between the years 2012 and 2019 were analysed. Pearson's correlation coefficients were calculated.RESULTS:All domains of trainee perception were correlated with excess mortality. Clinical supervision out of hours (R=-0.44; p<0.0001), teamwork (R=-0.36; p<0.0001) and clinical supervision at any time (R=-0.35; p<0.0001) were most strongly correlated. Most associations remained consistent year on year.CONCLUSION:Trainee doctor perceptions of clinical supervision, rota design and teamwork within the NHS are consistently correlated with excess patient mortality. Further exploration of these associations could identify opportunities for interventions to reduce excess patient mortality. Given the clinical significance of our findings, organisations should consider rapid implementation of evidence-based interventions where they exist.

ObjectivesThis study aimed to investigate whether components of junior doctor satisfaction are associated with patient mortality within the United Kingdom.MethodsWe conducted a cross-sectional study of publicly available data (the General Medical Council [GMC] National Survey and the Summary Hospital-level Mortality Indicator [SHMI]) pertaining to subjective physician trainee satisfaction and patient mortality within 80 United Kingdom-based healthcare institutions. The direction and strength of correlation between components of the GMC National Survey and relative patient mortality as described by the SHMI were calculated. Additional outcomes included mean GMC survey scores for reported domains and mean SHMI by healthcare institution.ResultsSHMI for included healthcare institutions ranged from 0.69 to 1.21 (mean [SD], 1.01 [0.1]). Mean GMC domain scores ranged between 44.61 and 88.62 (mean [SD], 71.16 [10.84]). Statistically significant correlations were observed for clinical supervision, clinical supervision out of hours, rota design, overall satisfaction, and teamwork. After application of Bonferroni correction, statistically significant correlations remained for both clinical supervision and clinical supervision out of hours.ConclusionsThere is a significant association between components of subjective trainee satisfaction and patient mortality within the United Kingdom. Further investigation to examine these relationships, perhaps to target intervention, may prevent avoidable patient harm.

Abstract Background and Purpose The use of patient reported outcomes measures (PROMs) may offer utility that are important for stroke survivors. This study assessed the PROMIS-10, which contains Mental health (MH) and Physical Health (PH) domains, with an additional five stroke specific questions. The aim of this study was to evaluate the association between the MH and PH measures following a stroke and pre-existing health conditions. Methods A multicentre prospective cohort study at 19 hospital sites across England and Wales during 2019 was conducted. The association between each PROMIS-10 domain and demographic and health conditions were calculated using a multilevel multivariable linear and present the adjusted mean difference (aMD). Results The study enrolled 549 stroke survivors within 14 days of the index event, 232 were women (42.3%) and with a mean age of 72.7 years (SD = 12.9, range 25 to 97). The MH domain was scored as poor in 3.9% of participants, and very good or excellent in almost a half (48.4%). In contrast the PH domain was scored as poor in 39.9%, compared to very good or excellent in 8.5%. The MH domain was associated with pre-existing diabetes (aMD = − 2.01; 95%CI -3.91, − 0.12; p = 0.04), previous stroke (aMD = − 3.62; 95%CI -5.86, − 1.39; p = 0.001), age (aMD = 0.07; 95%CI: 0.01, 0.14; p = 0.037), and female sex (aMD = 1.91; 95%CI 0.28, 3.54; p = 0.022). The PH domain was found to be associated with sex (female) (aMD = 2.09; 95%CI 0.54, 3.65; p = 0.008) and previous stroke (aMD = − 3.05; 95%CI -5.17, − 0.93; p = 0.005). Conclusions Almost half of stroke survivors reported poor PH using a PROM with less reporting poor MH. age, and sex were associated with both MH and PH domains, and additionally pre-exising diabetes and stroke were associated with poorer MH. Clinical management offers an opportunity to investigate and intervene to prevent long term poorer health in stroke survivors.

Cytokines are soluble proteins that mediate intercellular signaling regulating immune and inflammatory responses. Cytokine modulation represents a promising cancer immunotherapy approach for immune-mediated tumor regression. However, redundancy in cytokine signaling and cytokines' pleiotropy, narrow therapeutic window, systemic toxicity, short half-life and limited efficacy represent outstanding challenges for cytokine-based cancer immunotherapies. Recently, there has been interest in the paradoxical role of IL-10 in cancer, its controversial prognostic utility and novel strategies to enhance its therapeutic profile. Here, the authors review the literature surrounding the role of IL-10 within the tumor microenvironment, its prognostic correlates to cancer patient outcomes and its pro- and antitumor effects, and they assess the legitimacy of potential therapeutic strategies harnessing IL-10 by outlining the notable preclinical and clinical evidence to date.

Aims Depression is the single largest contributor to global disability. However, effective treatments are currently lacking, resulting in a significant burden of treatment-resistant depression (TRD). Psilocybin, a serotonergic psychedelic, found as the active compound in 'magic mushrooms', has been proposed as a novel therapeutic avenue for TRD. We aimed to evaluate the future feasibility and implications of psilocybin as a new antidepressant therapy. Method We reviewed and critically analysed the available literature on the efficacy and safety of psilocybin as a treatment for depression, and the potential pharmacological and psychological mechanisms of the therapeutic benefit. We discussed the relative contributions to this therapeutic effect of the pharmacological drug treatment, placebo effects, and the context and parameters of the psychotherapeutic experience. We reviewed legal, social, and economic barriers to primary research and clinical implementation. Result Psilocybin in combination with psychotherapy has been shown to be safe and effective in TRD. Its mechanism of action in TRD has not been fully elucidated, however reviewing functional neuroimaging studies demonstrated disparate short and long-term modifications of default mode network connectivity, suggested to represent a ‘reset’ mechanism of acute modular disintegration and subsequent reintegration which restores normal function, reviving emotional responsiveness. Research suggests psychedelic treatment induces lasting personality, belief and attitude changes. The psychedelic drug itself, the context of the psychotherapeutic experience, and the post-drug integration therapy all appear to have a significant role. Preparation prior to treatment, the environment, context and support during the psychedelic experience itself, and the following long-term integration and support process must be considered. Despite novel findings Psilocybin is a Schedule I drug; this imposes a persisting ethical barrier to clinical use. Prohibition of psilocybin results in high costs of drug supply, and potential for harmful drug-seeking behaviours. Therefore, complex socio-political factors currently limit wider implementation. Conclusion Psilocybin in combination with psychotherapy is safe and effective in TRD. The interacting and elusive therapeutic mechanisms have implications for clinical implementation. Preparation prior to treatment, the physical and social environment in which the psychedelic experience takes place, and long-term integration and support are considered to play a significant role. Optimisation of these parameters and cost-benefit analyses are required prior to this being feasible as a widely available therapy. Systemic legislative, political and social change will also be key to enable widespread clinical use. The promise of this therapy on a background of inadequate current antidepressant treatments indicates these must be a priority.

Future OncologyVol. 17, No. 31 EditorialNext-generation sequencing of cancer genomes: lessons learnedAmber E Corrigan, Robert Taylor & Kathrine S RallisAmber E Corrigan *Author for correspondence: E-mail Address: a.elyse.corrigan@gmail.comhttps://orcid.org/0000-0003-0636-0114GKT School of Medicine, King's College London, London, SE1 9RT, UK, Robert Taylor https://orcid.org/0000-0003-2782-4272Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society, Deutschordenstraße 46, 60528, Germany & Kathrine S Rallis https://orcid.org/0000-0003-1011-3220Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UKBarts Cancer Institute, Queen Mary University of London, London, EC1M 5PZ, UKPublished Online:25 Aug 2021https://doi.org/10.2217/fon-2021-0764AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: biomarkerscancergenomicsnext-generation sequencingNGSpersonalized medicineprecision medicinestratificationtumor clonal evolutiontumor heterogeneityReferences1. Metzker ML. Sequencing technologies - the next generation. Nat. Rev. Genet. 11(1), 31–46 (2010).Crossref, Medline, CAS, Google Scholar2. Mardis ER. A decade's perspective on DNA sequencing technology. Nature 470(7333), 198–203 (2011).Crossref, Medline, CAS, Google Scholar3. Thompson JF, Milos PM. The properties and applications of single-molecule DNA sequencing. Genome Biol. 12(2), 217 (2011).Crossref, Medline, CAS, Google Scholar4. Hammerman PS, Lawrence MS, Voet D et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489(7417), 519–525 (2012).Crossref, Medline, CAS, Google Scholar5. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5), 822–829 (2009).Crossref, Medline, CAS, Google Scholar6. Meacham CE, Morrison SJ. Tumor heterogeneity and cancer cell plasticity. Nature 501(7467), 328–337 (2013).Crossref, Medline, CAS, Google Scholar7. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501(7467), 338–345 (2013).Crossref, Medline, CAS, Google Scholar8. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15(2), 81–94 (2018).Crossref, Medline, CAS, Google Scholar9. Sun X, Yu Q. Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment. Acta Pharmacol. Sin. 36(10), 1219–1227 (2015).Crossref, Medline, CAS, Google Scholar10. Akbani R, Ng PKS, Werner HMJ et al. A pan-cancer proteomic perspective on The Cancer Genome Atlas. Nat. Commun. 5, 3887 (2014).Crossref, Medline, CAS, Google Scholar11. Gyanchandani R, Lin Y, Lin H-M et al. Intratumor heterogeneity affects gene expression profile test prognostic risk stratification in early breast cancer. Clin. Cancer Res. 22(21), 5362–5369 (2016).Crossref, Medline, CAS, Google Scholar12. Yun JW, Lee S, Ryu D et al. Biomarkers associated with tumor heterogeneity in prostate cancer. Transl. Oncol. 12(1), 43–48 (2018).Crossref, Medline, Google Scholar13. Charoentong P, Finotello F, Angelova M et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 18(1), 248–262 (2017).Crossref, Medline, CAS, Google Scholar14. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7(283), 283ra54 (2015).Crossref, Medline, Google Scholar15. McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168(4), 613–628 (2017).Crossref, Medline, CAS, Google Scholar16. Farooqui MZH, Valdez J, Martyr S et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 16(2), 169–176 (2015).Crossref, Medline, CAS, Google Scholar17. Ahn IE, Underbayev C, Albitar A et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood 129(11), 1469–1479 (2017).Crossref, Medline, CAS, Google Scholar18. Famà R, Bomben R, Rasi S et al. Ibrutinib-naïve chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance. Blood 124(25), 3831–3833 (2014).Crossref, Medline, CAS, Google Scholar19. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature 501(7467), 355–364 (2013).Crossref, Medline, CAS, Google Scholar20. Ramón y Cajal S, Sesé M, Capdevila C et al. Clinical implications of intratumor heterogeneity: challenges and opportunities. J. Mol. Med. (Berl) 98(2), 161–177 (2020).Crossref, Medline, Google Scholar21. Hiley CT, Swanton C. Spatial and temporal cancer evolution: causes and consequences of tumour diversity. Clin Med. 14(Suppl. 6), S33–S37 (2014).Crossref, Medline, Google Scholar22. Bardelli A, Pantel K. Liquid biopsies, what we do not know (yet). Cancer Cell. 31(2), 172–179 (2017).Crossref, Medline, CAS, Google Scholar23. Váraljai R, Horn S, Sucker A et al. Integrative genomic analyses of patient-matched intracranial and extracranial metastases reveal a novel brain-specific landscape of genetic variants in driver genes of malignant melanoma. Cancers (Basel). 13(4), 731 (2021).Crossref, Medline, CAS, Google Scholar24. Vignot S, Frampton GM, Soria J-C et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J. Clin. Oncol. 31(17), 2167–2172 (2013).Crossref, Medline, CAS, Google Scholar25. Brannon AR, Vakiani E, Sylvester BE et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 15(8), 454 (2014).Crossref, Medline, Google Scholar26. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct. Target Ther. 5, 28 (2020).Crossref, Medline, Google Scholar27. Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat. Rev. Cancer. 12(5), 323–334 (2012).Crossref, Medline, CAS, Google Scholar28. Eccles A, Challapalli A, Khan S, Barwick T, Mangar S. Thyroid lymphoma incidentally detected by 18F-fluorocholine (FCH) PET/CT. Clin. Nucl. Med. 38(9), 755–757 (2013).Crossref, Medline, Google Scholar29. Nakagawa H, Fujita M. Whole genome sequencing analysis for cancer genomics and precision medicine. Cancer Sci. 109(3), 513–522 (2018).Crossref, Medline, CAS, Google Scholar30. Colomer R, Mondejar R, Romero-Laorden N, Alfranca A, Sanchez-Madrid F, Quintela-Fandino M. When should we order a next generation sequencing test in a patient with cancer? E. Clinical Medicine 25(100487), (2020).Google ScholarFiguresReferencesRelatedDetails Vol. 17, No. 31 STAY CONNECTED Metrics Downloaded 73 times History Published online 25 August 2021 Published in print November 2021 Information© 2021 Future Medicine LtdKeywordsbiomarkerscancergenomicsnext-generation sequencingNGSpersonalized medicineprecision medicinestratificationtumor clonal evolutiontumor heterogeneityFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Background and Purpose: The use of patient reported outcomes measures (PROMs) may offer utility and provide outcome measures that are important for stroke survivors. This study used a stroke specific PROM, which contains Mental health (MH) and Physical Health (PH). The primary aim of this study was to assess the association between the MH and PH measures following a stroke and preexisting health conditions. Methods: A multicenter prospective cohort study at 19 hospital sites across England and Wales during 2019 was conducted. Prevalence of morbidity within PROMs was estimated with 95% confidence intervals (95% CI). The association between each PROM domain and demographic and health conditions were calculated using a multilevel multivariable linear model fitting the adjusted mean difference (aMD). Results: PROM morbidity was high post stroke; 93.2% of the participants reported combined post stroke PROM morbidity. The MH domain was associated with pre-existing: diabetes, previous stroke, age, and sex. The PH domain was found to be associated with gender (female) and previous stroke, Conclusions: Stroke survivors ubiquitously suffer morbidity. Risk factors associated with worsening MH and PH morbidity have implications in clinical management as they offer an opportunity to intervene, particularly to prevent long term mental health. PROMs provide useful outcome measure that matter to stroke survivors.

Cancer immunotherapy is an evolving field of research. Cytokines have been conceptualized as an anticancer therapy for longer than most other cancer immunotherapy modalities. Yet, to date, only two cytokines are FDA-approved: IFN-α and IL-2. Despite the initial breakthrough, both agents have been superseded by other, more efficacious agents such as immune checkpoint inhibitors. Several issues persist with cytokine-based cancer therapies; these are broadly categorised into a) high toxicity and b) low efficacy. Despite the only moderate benefits with early cytokine-based cancer therapies, advances in molecular engineering, genomics, and molecular analysis hold promise to optimise and reinstate cytokine-based therapies in future clinical practice. This review considers five important concepts for the successful clinical application of cytokine-based cancer therapies including: (i) improving pharmacokinetics and pharmacodynamics, (ii) improving local administration strategies, (iii) understanding context-dependent interactions in the tumour-microenvironment, (iv) elucidating the role of genetic polymorphisms, and (v) optimising combination therapies. IL-10 has been the focus of attention in recent years and is discussed herein as an example.

Purpose Self-directed learning (SDL) has been increasingly emphasized within medical education. However, little is known about the SDL resources medical students use. This study aimed to identify patterns in medical students’ SDL behaviors, their SDL resource choices, factors motivating these choices, and the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on these variables. Methods An online cross-sectional survey comprising multiple-choice, ranked, and free-text response questions were disseminated to medical students across all 41 UK medical schools between April and July 2020. Independent study hours and sources of study materials prior to and during the COVID-19 pandemic were compared. Motivational factors guiding resource choices and awareness of Free Open Access Meducation were also investigated. Results The target sample was 75 students per medical school across a total of 41 medical schools within the United Kingdom (3,075 total students), and 1,564 responses were analyzed. University-provided information comprised the most commonly used component of independent study time, but a minority of total independent study time. Independent study time increased as a result of the COVID-19 pandemic (P<0.001). All sub-cohorts except males reported a significant increase in the use of resources such as free websites and question banks (P<0.05) and paid websites (P<0.05) as a result of the pandemic. Accessibility was the most influential factor guiding resource choice (Friedman’s μrank=3.97, P<0.001). Conclusion The use of learning resources independent of university provision is increasing. Educators must ensure equitable access to such materials while supporting students in making informed choices regarding their independent study behaviors.