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Policy Points: Significant advances in clinical medicine that have broader societal relevance may be less accessible to population health researchers and policymakers because of increased specialization within fields. We describe important recent clinical advances and discuss their broader societal impact. These advances include more expansive strategies for disease prevention, the rise of precision medicine, applications of human microbiome research, and new and highly successful treatments for hepatitis C infection. These recent developments in clinical research raise important issues surrounding health care costs and equitable resource allocation that necessitate an ongoing dialogue among the fields of clinical medicine, population health, and health policy. Context: Developments in clinical medicine have important implications for population health, and there is a need for interdisciplinary engagement among clinical medicine, the social sciences, and public health research. The aim of this article is to help bridge the divide between these fields by exploring major recent advances in clinical medicine that have important implications for population health. Methods: We reviewed the most cited articles published from 2010 to 2015 in 5 high‐impact clinical journals and selected 5 randomized controlled trials and 2 related clinical practice guidelines that are broadly relevant to population health and policy. Findings: We discuss the following themes: (1) expanding indications for drug therapy and the inherent medicalization of the population as highlighted by studies and clinical guidelines supporting lower blood pressure targets or widespread statin use; (2) the tension in nutritional research between quantifying the impact of isolated nutrients and studying specific foods and dietary patterns, for example, the role of the Mediterranean diet in the primary prevention of cardiovascular disease; (3) the issue of high medication costs and the challenge of providing equitable access raised by the development of new and effective treatments for hepatitis C infection; (4) emerging clinical applications of research on the human microbiome as illustrated by fecal transplant to treat Clostridium difficile infections; and (5) the promise and limitations of precision medicine as demonstrated by the rise of novel targeted therapies in oncology. Conclusions: These developments in clinical science hold promise for improving individual and population health and raise important questions about resource allocation, the role of prevention, and health disparities. [ABSTRACT FROM AUTHOR]

Importance: With the growing use of large language models (LLMs) in education and health care settings, it is important to ensure that the information they generate is diverse and equitable, to avoid reinforcing or creating stereotypes that may influence the aspirations of upcoming generations., Objective: To evaluate the gender representation of LLM-generated stories involving medical doctors, surgeons, and nurses and to investigate the association of varying personality and professional seniority descriptors with the gender proportions for these professions., Design, Setting, and Participants: This is a cross-sectional simulation study of publicly accessible LLMs, accessed from December 2023 to January 2024. GPT-3.5-turbo and GPT-4 (OpenAI), Gemini-pro (Google), and Llama-2-70B-chat (Meta) were prompted to generate 500 stories featuring medical doctors, surgeons, and nurses for a total 6000 stories. A further 43 200 prompts were submitted to the LLMs containing varying descriptors of personality (agreeableness, neuroticism, extraversion, conscientiousness, and openness) and professional seniority., Main Outcomes and Measures: The primary outcome was the gender proportion (she/her vs he/him) within stories generated by LLMs about medical doctors, surgeons, and nurses, through analyzing the pronouns contained within the stories using χ2 analyses. The pronoun proportions for each health care profession were compared with US Census data by descriptive statistics and χ2 tests., Results: In the initial 6000 prompts submitted to the LLMs, 98% of nurses were referred to by she/her pronouns. The representation of she/her for medical doctors ranged from 50% to 84%, and that for surgeons ranged from 36% to 80%. In the 43 200 additional prompts containing personality and seniority descriptors, stories of medical doctors and surgeons with higher agreeableness, openness, and conscientiousness, as well as lower neuroticism, resulted in higher she/her (reduced he/him) representation. For several LLMs, stories focusing on senior medical doctors and surgeons were less likely to be she/her than stories focusing on junior medical doctors and surgeons., Conclusions and Relevance: This cross-sectional study highlights the need for LLM developers to update their tools for equitable and diverse gender representation in essential health care roles, including medical doctors, surgeons, and nurses. As LLMs become increasingly adopted throughout health care and education, continuous monitoring of these tools is needed to ensure that they reflect a diverse workforce, capable of serving society's needs effectively.

This retrospective cross-sectional study investigates the impact of laboratory-specific hemoglobin reference intervals on electronic consultation (eConsult) referral patterns for suspected anemia and elevated hemoglobin at a tertiary care center in London, Ontario that serves Southwestern Ontario. The study analyzed referrals through the Ontario Telemedicine Network's eConsult platform for hemoglobin abnormalities, excluding patients under 18 years old, between July 1, 2019, and June 30, 2023.The main outcome measures were influence of hemoglobin reference intervals on the referral patterns for suspected anemia and elevated hemoglobin, as well as the extent of pre-referral laboratory testing. Of the 619 eConsults reviewed, 251 referrals for suspected anemia and 93 for elevated hemoglobin were analyzed. Referral patterns showed significant variance in hemoglobin levels based on different laboratory thresholds. Referrals for suspected anemia in females from laboratories whose lower limit was 120 g/L or greater had a hemoglobin concentration 7.5 g/L greater than referrals that used laboratories with a threshold lower than 120 g/L. The study also identified potential areas for improvement in pre-referral investigations; 44% of eConsults did not provide a ferritin level, 53% were missing a B12 level, and 81% were missing a reticulocyte count. In conclusion, laboratory reference intervals for hemoglobin significantly influence referral patterns for suspected hemoglobin abnormalities in Ontario's eConsult system. There is a need for standardized reference intervals and comprehensive pre-referral testing to avoid unnecessary medicalization and referrals. We propose an anemia management algorithm to guide primary care providers in the pre-referral investigation process., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ahmad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It is unknown to what extent medical researchers generalize study findings beyond their samples when their sample size, sample diversity, or knowledge of conditions that support external validity do not warrant it. It is also unknown to what extent medical researchers describe their results with precise quantifications or unquantified generalizations, i.e., generics, that can obscure variations between individuals. We therefore systematically reviewed all prospective studies (n = 533) published in the top four highest ranking medical journals, Lancet, New England Journal of Medicine (NEJM), Journal of the American Medical Association (JAMA), and the British Medical Journal (BMJ), from January 2022 to May 2023. We additionally reviewed all NEJM Journal Watch clinical research summaries (n = 143) published during the same time. Of all research articles reporting prospective studies, 52.5% included generalizations beyond specific national study populations, with the numbers of articles with generics varying significantly between journals (JAMA = 12%; Lancet = 77%) (p < 0.001, V = 0.48). There was no evidence that articles containing broader generalizations or generics were correlated with larger or more nationally diverse samples. Moreover, only 10.2% of articles with generalizations beyond specific national populations reported external validity strengthening factors that could potentially support such extrapolations. There was no evidence that original research articles and NEJM Journal Watch summaries intended for practitioners differed in their use of broad generalizations, including generics. Finally, from the journal with the highest citation impact, articles containing broader conclusions were correlated with more citations. Since there was no evidence that studies with generalizations beyond specific national study populations or with generics were associated with larger, more nationally diverse samples, or with reports of population similarity that may permit extensions of conclusions, our findings suggest that the generalizations in many articles were insufficiently supported. Caution against overly broad generalizations in medical research is warranted., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Peters et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Objectives: To evaluate the effectiveness of safeguards to prevent large language models (LLMs) from being misused to generate health disinformation, and to evaluate the transparency of artificial intelligence (AI) developers regarding their risk mitigation processes against observed vulnerabilities., Design: Repeated cross sectional analysis., Setting: Publicly accessible LLMs., Methods: In a repeated cross sectional analysis, four LLMs (via chatbots/assistant interfaces) were evaluated: OpenAI's GPT-4 (via ChatGPT and Microsoft's Copilot), Google's PaLM 2 and newly released Gemini Pro (via Bard), Anthropic's Claude 2 (via Poe), and Meta's Llama 2 (via HuggingChat). In September 2023, these LLMs were prompted to generate health disinformation on two topics: sunscreen as a cause of skin cancer and the alkaline diet as a cancer cure. Jailbreaking techniques (ie, attempts to bypass safeguards) were evaluated if required. For LLMs with observed safeguarding vulnerabilities, the processes for reporting outputs of concern were audited. 12 weeks after initial investigations, the disinformation generation capabilities of the LLMs were re-evaluated to assess any subsequent improvements in safeguards., Main Outcome Measures: The main outcome measures were whether safeguards prevented the generation of health disinformation, and the transparency of risk mitigation processes against health disinformation., Results: Claude 2 (via Poe) declined 130 prompts submitted across the two study timepoints requesting the generation of content claiming that sunscreen causes skin cancer or that the alkaline diet is a cure for cancer, even with jailbreaking attempts. GPT-4 (via Copilot) initially refused to generate health disinformation, even with jailbreaking attempts-although this was not the case at 12 weeks. In contrast, GPT-4 (via ChatGPT), PaLM 2/Gemini Pro (via Bard), and Llama 2 (via HuggingChat) consistently generated health disinformation blogs. In September 2023 evaluations, these LLMs facilitated the generation of 113 unique cancer disinformation blogs, totalling more than 40 000 words, without requiring jailbreaking attempts. The refusal rate across the evaluation timepoints for these LLMs was only 5% (7 of 150), and as prompted the LLM generated blogs incorporated attention grabbing titles, authentic looking (fake or fictional) references, fabricated testimonials from patients and clinicians, and they targeted diverse demographic groups. Although each LLM evaluated had mechanisms to report observed outputs of concern, the developers did not respond when observations of vulnerabilities were reported., Conclusions: This study found that although effective safeguards are feasible to prevent LLMs from being misused to generate health disinformation, they were inconsistently implemented. Furthermore, effective processes for reporting safeguard problems were lacking. Enhanced regulation, transparency, and routine auditing are required to help prevent LLMs from contributing to the mass generation of health disinformation., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: AMH holds an emerging leader investigator fellowship from the National Health and Medical Research Council (NHMRC), Australia; NDM is supported by a NHMRC postgraduate scholarship, Australia; MJS is supported by a Beat Cancer research fellowship from the Cancer Council South Australia; BDM’s PhD scholarship is supported by The Beat Cancer Project, Cancer Council South Australia, and the NHMRC, Australia; no support from any other organisation for the submitted work; AR and MJS are recipients of investigator initiated funding for research outside the scope of the current study from AstraZeneca, Boehringer Ingelheim, Pfizer, and Takeda; and AR is a recipient of speaker fees from Boehringer Ingelheim and Genentech outside the scope of the current study. There are no financial relationships with any other organisations that might have an interest in the submitted work in the previous three years to declare; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Thrombocytosis is a common reason for referral to Hematology. Differentiating between secondary causes of thrombocytosis and essential thrombocythemia (ET) is often clinically challenging. A practical diagnostic approach to identify secondary thrombocytosis could reduce overinvestigation such as next generation sequencing (NGS) panel., Methods and Results: All adult patients with thrombocytosis (≥450 × 10 9 /L) who underwent molecular testing at a single tertiary care centre between January 1, 2018 and May 31, 2021 were evaluated. Clinical and laboratory variables were compared between patients with secondary thrombocytosis vs. ET. Clinical variables included smoking, thrombosis, splenectomy, active malignancy, chronic inflammatory disease, and iron deficiency anemia. Laboratory variables included complete blood count (CBC), ferritin, and myeloid mutations detected by NGS. The overall yield of molecular testing was 52.4%; 92.1% of which were mutations in JAK2 , CALR , and/or MPL . Clinical factors predictive of ET included history of arterial thrombosis ( p < 0.05); active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency were associated with secondary thrombocytosis ( p < 0.05). A diagnosis of ET was associated with higher hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV), while secondary thrombocytosis was associated with higher body mass index, white blood cells, and neutrophils ( p < 0.01)., Conclusion: A practical approach to investigating patients with persistent thrombocytosis based on clinical characteristics such as active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency may assist in accurately identifying patients more likely to have secondary causes of thrombocytosis and reduce overinvestigation, particularly costly molecular testing., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Ala Almanaseer et al.)

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer., (© 2023 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

Background: Erythrocytosis, most often measured as an increase in hemoglobin and/or hematocrit, is a common reason for referral to internal medicine and hematology clinics and a rational approach is required to effectively identify patients with polycythemia vera while avoiding over-investigation., Aim: We aimed to develop and validate a simple rule to predict JAK2 mutation positivity based on complete blood count parameters to aid in the diagnostic approach to patients referred for elevated hemoglobin., Setting: Internal medicine and hematology clinics at an academic tertiary referral center., Participants: The JAK2 Prediction Cohort (JAKPOT), a large retrospective cohort (n = 901) of patients evaluated by internal medicine and hematology specialists for elevated hemoglobin., Design: JAK2 mutation analysis was performed in all patients and clinical and laboratory variables were collected. Patients were randomly divided into derivation and validation cohorts. A prediction rule was developed using data from the derivation cohort and tested in the validation cohort., Key Results: The JAKPOT prediction rule included three variables: (i) red blood cell count >6.45×10 12 /L, (ii) platelets >350×10 9 /L, and (iii) neutrophils >6.2×10 9 /L; absence of all criteria was effective at ruling out JAK2-positivity with sensitivities 94.7% and 100%, and negative predictive values of 98.8% and 100% in the derivation and validation cohorts, respectively, with an overall low false negative rate of 0.4%. The rule was validated for three different methods of JAK2 testing. Applying this rule to our entire cohort would have resulted in over 50% fewer tests., Conclusion: In patients with elevated hemoglobin, the use of a simple prediction rule helps to accurately identify patients with a low likelihood of having a JAK2 mutation, potentially limiting costly over-investigation in this common referral population., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Issue : Technological innovation is accelerating, creating less time to reflect on the impact new technologies will have on the medical profession. Modern technologies are becoming increasingly embedded in routine medical practice with far-reaching impacts on the patient-physician relationship and the very essence of the health professions. These impacts are often difficult to predict and can create unintended consequences for medical education. This article is driven by a main question: How do we prepare trainees to critically assess technologies that we cannot foresee and effectively use technology to support equitable and compassionate care? Evidence : We translate insights from the philosophy of technology into a proposal for integrating critical technical consciousness in medical curricula. We identify three areas required to develop critical consciousness with regard to emerging technologies. The first area is technical literacy, which involves not just knowing how to use technology, but also understanding its limitations and appropriate contexts for use. The second area is the ability to assess the social impact of technology. This practice requires understanding that while technification creates new possibilities it can also have adverse, unintended consequences. The third area is critical reflection on the relationship between 'the human' and 'the technical' as it relates to the values of the medical profession and professional identity formation. Human and technology are two sides of the same coin; therefore, thinking critically about technology also forces us to think about what we consider 'the human side of medicine'. Implications : Critical technical consciousness can be fostered through an educational program underpinned by the recognition that, although technological innovation can create new possibilities for healing, technology is never neutral. Rather, it is imperative to emphasize that technology is interwoven with the social fabric that is essential to healing. Like medication, technology can be both potion and poison.

Generalizations in medical research can be informative, but also misleading. Building on recent work in the philosophy of science and ethics of communication, I offer a novel analysis of common generalizations in clinical trials as generics in natural language. Generics, which express generalizations without terms of quantification, have attracted considerable attention from philosophers, psychologists, and linguists. My analysis draws on probabilistic and contextual features of generics to diagnose how these generalizations function and malfunction across communicative contexts in medicine. Given a high risk of misinterpretation ("slippage"), I recommend avoidance of generic claims about medical interventions in public contexts, exemplified by clinical trials and medical research more generally. Generics should only be used with vigilance in private contexts, exemplified by the physician-patient encounter. My analysis provides tools to support vigilance when communicating with generics, suggests new norms for public science communication, and raises deeper questions in the ethics of clinical communication.

Introduction: T-cell clonality testing by T-cell receptor (TCR) gene rearrangement is key to the diagnosis of T-cell lymphoproliferative disorders such as T-cell large granular lymphocytic (T-LGL) leukemia. Benign clonal T-cell expansions, however, are commonly found in patients without identifiable disease, a condition referred to as T-cell clones of uncertain significance (T-CUS). In practice, T-cell clonality testing is performed for a range of reasons and results are often challenging to interpret given the overlap between benign and malignant clonal T-cell proliferations and uncertainties in the management of T-CUS., Methods: We conducted a 5-year retrospective cohort study of 211 consecutive patients who underwent PCR-based T-cell clonality testing for suspected T-LGL leukemia at our institution to characterize the use of T-cell clonality testing and its impact on patient management., Results: Overall, 46.4% (n = 98) of individuals tested had a clonal T-cell population identified. Patients with a monoclonal T-cell population were more likely to be older, have rheumatoid arthritis and have higher lymphocyte counts compared to patients with polyclonal populations. The majority of patients eventually diagnosed and treated for T-LGL leukemia had rheumatoid arthritis and lower neutrophil counts compared to untreated patients with monoclonal T-cell populations. A diagnosis of T-LGL leukemia was made in only a minority of patients (n = 48, 22.7%), and only a small proportion were treated (n = 17, 8.1%)., Conclusion: Our study suggests that T-cell clonality testing most commonly identifies incidental T-cell clones with only a minority of patients receiving a diagnosis of T-LGL leukemia and fewer requiring active treatment. These finding indicate an opportunity to improve utilization of T-cell clonality testing in clinical practice to better target patients where the results of testing would impact clinical management., (© 2022 John Wiley & Sons Ltd.)

Background: Molecular testing for JAK2 mutations is part of the standard diagnostic workup for patients with suspected polycythemia vera. We sought to characterize evolving practice patterns in the investigation of erythrocytosis and the prevalence of secondary causes, including use of medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, among patients who underwent molecular testing., Methods: We reviewed charts of all consecutive patients investigated for erythrocytosis (hemoglobin > 160 g/L for women, > 165 g/L for men) with JAK2 testing between 2015 and 2021 at London Health Sciences Centre, a tertiary referral centre in Ontario, Canada, to assess changes in rates of JAK2 mutation positivity, average hemoglobin levels and the prevalence of secondary causes of erythrocytosis., Results: A total of 891 patients with erythrocytosis underwent JAK2 mutation testing with an increase in number of tests (particularly from 2017 to 2018), a decrease in the rate of JAK2 positivity and similar average hemoglobin levels over the study period. We observed a high proportion of patients with secondary causes of erythrocytosis, ranging from 59% to 74% over the study period, including medications associated with erythrocytosis, namely testosterone (6%-11%) and SGLT2 inhibitors (2%-19%). Stopping SGLT2 inhibitors was associated with a significant decrease in hemoglobin levels (mean -14.7 g/L, 95% confidence interval -18.9 to -10.5 g/L) compared with continuation., Interpretation: Use of SGLT2 inhibitors may be a common and underrecognized secondary cause of elevated hemoglobin levels in patients investigated for erythrocytosis. Our findings underscore the importance of a detailed medical history to support judicious use of molecular testing, in adherence with the current guideline on the investigation of erythrocytosis., Competing Interests: Competing interests: None declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: The field of oncology is at the forefront of advances in artificial intelligence (AI) in health care, providing an opportunity to examine the early integration of these technologies in clinical research and patient care. Hope that AI will revolutionize health care delivery and improve clinical outcomes has been accompanied by concerns about the impact of these technologies on health equity., Objective: We aimed to conduct a scoping review of the literature to address the question, "What are the current and potential impacts of AI technologies on health equity in oncology?", Methods: Following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines for scoping reviews, we systematically searched MEDLINE and Embase electronic databases from January 2000 to August 2021 for records engaging with key concepts of AI, health equity, and oncology. We included all English-language articles that engaged with the 3 key concepts. Articles were analyzed qualitatively for themes pertaining to the influence of AI on health equity in oncology., Results: Of the 14,011 records, 133 (0.95%) identified from our review were included. We identified 3 general themes in the literature: the use of AI to reduce health care disparities (58/133, 43.6%), concerns surrounding AI technologies and bias (16/133, 12.1%), and the use of AI to examine biological and social determinants of health (55/133, 41.4%). A total of 3% (4/133) of articles focused on many of these themes., Conclusions: Our scoping review revealed 3 main themes on the impact of AI on health equity in oncology, which relate to AI's ability to help address health disparities, its potential to mitigate or exacerbate bias, and its capability to help elucidate determinants of health. Gaps in the literature included a lack of discussion of ethical challenges with the application of AI technologies in low- and middle-income countries, lack of discussion of problems of bias in AI algorithms, and a lack of justification for the use of AI technologies over traditional statistical methods to address specific research questions in oncology. Our review highlights a need to address these gaps to ensure a more equitable integration of AI in cancer research and clinical practice. The limitations of our study include its exploratory nature, its focus on oncology as opposed to all health care sectors, and its analysis of solely English-language articles., (©Paul Istasy, Wen Shen Lee, Alla Iansavichene, Ross Upshur, Bishal Gyawali, Jacquelyn Burkell, Bekim Sadikovic, Alejandro Lazo-Langner, Benjamin Chin-Yee. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 01.11.2022.)

Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common JAK2 V617F mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. Method: A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant "hotspot" regions) and a panel of 29 fusion driver genes (>600 fusion partners). Results: &nbsp; JAK2 mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for JAK2 V617F , while one patient had a JAK2 exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of JAK2 -positive patients: TET2 (11; 19%), DNMT3A (2;3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%), and ZRSR2 (1; 1.7%). Diagnosis of PV was suspected in 2 JAK2 -negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the SRSF2 and TET2 genes, and the other patient carried mutations in the SRSF2, IDH2, and ASXL1 genes. Three JAK2 -negative patients with elevated hemoglobin who tested positive for BCR/ABL1 fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 JAK2 -negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Conclusion: Mutations other than JAK2 mutations were frequently identified in patients referred for erythrocytosis, with mutations in the TET2, DNMT3A, and ASXL1 genes being detected in 34.5% of JAK2 -positive PV patients. The presence of additional mutations, such as ASXL1 mutations, in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP).

Introduction: In most laboratories, next generation sequencing (NGS) has been added without consideration for redundancy compared to conventional cytogenetics (CG). We tested a streamlined approach to genomic testing in patients with suspected myeloid and plasma cell neoplasms using next generation sequencing ("NGS first") as the primary testing modality and limiting cytogenetics (CG) to samples with morphologic abnormalities in the marrow aspirate., Methods: Based on morphologic interpretation of bone marrow aspirate and flow cytometry, samples were triaged into four groups: (a) Samples with dysplasia or excess blasts had both NGS and karyotyping; (b) Samples without excess blasts or dysplasia had NGS only; (c) Repeat samples with previous NGS and/or CG studies were not retested; (d) Samples for suspected myeloma with less than 5% plasma cell had CG testing cancelled., Results: Seven hundred eleven adult bone marrow (BM) samples met the study criteria. The NGS first algorithm eliminated CG testing in 229/303 (75.6%) of patients, primarily by reducing repeat testing. Potential cost avoided was approximately $124 000 per annum. Hematologists overruled the triage comment in only 11/303 (3.6%) cases requesting CG testing for a specific indication., Conclusions: Utilizing NGS as the primary genomic testing modality NGS was feasible and well accepted, reducing over three quarters of all CG requests and improving the financial case for adoption of NGS. Key factors for the success of this study were collaboration of clinical and genomic diagnostic teams in developing the algorithm, rapid turnaround time for BM interpretation for triage, and communication between laboratories., (© 2021 John Wiley & Sons Ltd.)

Evidence based medicine (EBM) has been synonymous to delivery of quality care for almost thirty years. Since the movement's inception, the assumption has been that decisions based on high quality evidence would translate to better care for patients. Despite EBM's many attractive features and the substantive attention it has received in the contemporary clinical and medical education literature, how it is defined and operationalized as a component of training is often unclear and problematic. How to practice EBM is not well articulated in the literature; therefore, it becomes difficult to teach and equally challenging to assess. In this paper, we put forward a call for deeper consideration of how EBM is taught, and for clarification on how it is defined and operationalized in medical education. In preparing this paper, we considered questions such as what it means to practice EBM, the role that medical education plays in helping realize EBM, how the teaching of EBM can change to reflect recent developments in clinical practice and education, and whether transformations in the practice of medicine necessitate a change in how we teach EBM. We end with four avenues that may be pursued to advance the teaching of EBM in medical education: (1) consensus on what we mean by EBM; (2) clear articulation of EBM-associated competencies; (3) empirically and theoretically supported means of promoting EBM competencies; (4) ways to assess both skill acquisition and use of EBM. We discuss implications for educators of EBM., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

BACKGROUNDThe role of humoral immunity in COVID-19 is not fully understood, owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.METHODSUsing SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients' plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.RESULTSWe identified linear epitopes from the spike (S) and nucleocapsid (N) proteins and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S-811-825, S-881-895, and N-156-170 epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes.CONCLUSIONEpitope-resolved antibody testing not only affords a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, but it also may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern in both the peptide array and latex agglutination formats.FUNDINGOntario Research Fund (ORF) COVID-19 Rapid Research Fund, Toronto COVID-19 Action Fund, Western University, Lawson Health Research Institute, London Health Sciences Foundation, and Academic Medical Organization of Southwestern Ontario (AMOSO) Innovation Fund.

We have developed a rapid, accurate, and cost-effective serologic test for SARS-CoV-2 virus, which caused the COVID-19 pandemic, on the basis of antibody-dependent agglutination of antigen-coated latex particles. When validated using plasma samples that are positive or negative for SARS-CoV-2, the agglutination assay detected antibodies against the receptor-binding domain of the spike (S-RBD) or the nucleocapsid protein of SARS-CoV-2 with 100% specificity and ∼98% sensitivity. Furthermore, we found that the strength of the S-RBD antibody response measured by the agglutination assay correlated with the efficiency of the plasma in blocking RBD binding to the angiotensin-converting enzyme 2 in a surrogate neutralization assay, suggesting that the agglutination assay might be used to identify individuals with virus-neutralizing antibodies. Intriguingly, we found that >92% of patients had detectable antibodies on the day of a positive viral RNA test, suggesting that the agglutination antibody test might complement RNA testing for the diagnosis of SARS-CoV-2 infection., Competing Interests: S.E., C.V., and S.S.-C.L. are co-inventors in a US Provisional patent application on the agglutination assay submitted by Western University., (© 2021 The Authors.)

This article explores conceptual and methodological challenges surrounding the recovery of patients' voices in the history of medicine. We examine the debate that followed Roy Porter's seminal article, 'The Patient's View: Doing Medical History from Below' (1985). Porter argued that patients should be given a central role in medical history, aiming to restore to patients a voice and agency that is often lost in 'physician-centered' historical narratives. His work carried significant influence but also sparked an ongoing debate about the possibility of conducting 'patient-centered' history of medicine. The growth of the medical humanities has afforded renewed attention to patient narratives, supporting the need to recognise patients' voices in contemporary healthcare and medical education. However, several barriers complicate and problematise the expansion of a patient-centred epistemology across historical periods. Postmodern critics have expressed scepticism that 'the patient's view' can be recovered from history, with some claiming that 'the patient' is a construct of the 'medical gaze' whose subjectivity cannot be reconstituted outside of sociohistorical discourses of knowledge and power. Psychiatry in the mid-20th century presents a particular challenge for patient-centred history. We discuss the influence of postmodern theorists, especially Michel Foucault, whose work is seen as undermining the possibility of a patient-centred epistemology. We argue against Foucault's erasure of the patient, and instead explore alternate constructivist epistemologies, focusing on the hermeneutics of Hans-Georg Gadamer and dialogism of Mikhail Bakhtin, to help address historiographical challenges in recovering 'the patient's view'. To illustrate the value of Gadamerian and Bakhtinian approaches, we apply them to a case study from the Verdun Protestant Hospital (Québec, Canada) from 1941 to 1956, which sheds light on the introduction of the first antipsychotic, chlorpromazine, into clinical practice. We highlight how Gadamer's hermeneutics and Bakhtin's dialogism together offer insights into patient perspectives during this liminal period in the history of psychiatry., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Drawing from the philosophical work of Hans-Georg Gadamer and the perspectives of theorists Mikhail Bakhtin and Kenneth Burke, the aim of this paper is to critically reflect on the meaning of the word "shared.", Method: The authors draw on the concept of epistemic justice, which they argue permeates the clinical encounter, to discuss how various forms of, and claims to, knowledge may influence the attainement of shared decision-making in health care contexts. The specific objectives are twofold: first, the authors draw key concepts from key Gadamerian, Burkean, and Bakhtinian philosophical perspectives to consider shared decision-making in relation to two types of epistemic injustice: testimonial and hermeneutic epistemic injustice. Second, building on philosopher Paulo Freire's critical pedagogy, the authors emphasize that major changes in educational structures and systems are required to promote the critical reflexivity required to address issues of epistemic justice, in the broader pursuit of authentic shared decision-making., Results: They propose three main areas of focus for helath professions education: (a) changes in content (moving from a focus on biomedical knowledge to more content on social sciences) and methods of teaching (more dialogue and the creation of moments of dissonance); (b) a re-examination of teachers' role in promoting epistemic justice; and (c) inclusion of patients as partners., Conclusions: Without major transformation in what, how, and with whom we teach, future clinicians may be unprepared to enact shared decision-making in a manner that does justice to the various ways of knowing., (© 2020 John Wiley & Sons, Ltd.)

Genomic technologies are revolutionizing the practice of haematology-oncology, leading to improved disease detection, more accurate prognostication and targeted treatment decisions. These advances, however, have also introduced new clinical challenges, which include problems of prognostic underdetermination and its attendant risks of over- and undertreatment. Genomic data is generated from different technologies, from cytogenetics to next-generation sequencing, which are often interpreted interchangeably and in a binary fashion-as the presence or absence of a given chromosomal deletion or mutation-an oversimplification which may lead to mistaken prognosis. We discuss the clinical use of one such prognostic marker, represented by sequence and copy number alterations in TP53, located on chromosome 17p. Mutations in TP53 are strongly linked to poor prognosis in a variety of haematological malignancies, including chronic lymphocytic leukaemia (CLL). We review studies in CLL which utilize the 17p deletion or TP53 mutations for prognostic stratification with specific focus on the technologies used for detection, the thresholds established for clinical significance, and the clinical contexts in which these alterations are identified. The case of CLL illustrates issues arising from simplistic, binary interpretation of genetic testing and highlights the need to apply a critical lens when incorporating genomics into prognostic models., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Crusted scabies is a rare disease variant associated with T-cell dysregulation. Transplant patients are at risk of developing crusted scabies as a consequence of their immunosuppressive regimens. We report a case of crusted scabies presenting with recurrent septicemia in a 65-year-old renal transplant recipient, treated with daily ivermectin for 7 days after initial failure of weekly ivermectin dosing. A literature review of crusted scabies in transplant recipients consisting of 19 cases reports was summarized. Pruritus was common, and initial misdiagnosis was frequent. Most were treated with topical therapy, with one-third receiving ivermectin. Three of seven cases presenting with a concomitant infection died. Crusted scabies is commonly misdiagnosed in transplant recipients owing to its rarity, varied appearance, and different skin distributions. It should be considered in the differential diagnosis of transplant recipients presenting with rash and pruritus, given its association with secondary infection and subsequent mortality., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Medicine in the twenty-first century faces an 'identity crisis,' as it grapples with the emergence of various 'ways of knowing,' from evidence-based and translational medicine, to narrative-based and personalized medicine. While each of these approaches has uniquely contributed to the advancement of patient care, this pluralism is not without tension. Evidence-based medicine is not necessary individualized; personalized medicine may be individualized but is not necessarily person-centered. As novel technologies and big data continue to proliferate today, the focus of medical practice is shifting away from the dialogic encounter between doctor and patient, threatening the loss of humanism that many view as integral to medicine's identity. As medical trainees, we struggle to synthesize medicine's diverse and evolving 'ways of knowing' and to create a vision of doctoring that integrates new forms of medical knowledge into the provision of person-centered care. In search of answers, we turned to twentieth-century philosopher Hans-Georg Gadamer, whose unique outlook on "health" and "healing," we believe, offers a way forward in navigating medicine's 'messy pluralism.' Drawing inspiration from Gadamer's emphasis on dialogue and 'practical wisdom' (phronesis), we initiated a dialogue with the dean of our medical school to address the question of how medical trainees and practicing clinicians alike can work to create a more harmonious pluralism in medicine today. We propose that implementing a pluralistic approach ultimately entails 'bridging' the current divide between scientific theory and the practical art of healing, and involves an iterative and dialogic process of asking questions and seeking answers.

The rise of big data and artificial intelligence (AI) in health care has engendered considerable excitement, claiming to improve approaches to diagnosis, prognosis, and treatment. Amidst the enthusiasm, the philosophical assumptions that underlie the big data and AI movement in medicine are rarely examined. This essay outlines three philosophical challenges faced by this movement: (1) the epistemological-ontological problem arising from the theory-ladenness of big data and measurement; (2) the epistemological-logical problem resulting from the inherent limitations of algorithms and attendant issues of reliability and interpretability; and (3) the phenomenological problem concerning the irreducibility of human experience to quantitative data. These philosophical issues demonstrate several important challenges for these technologies that must be considered prior to their integration into clinical care. Our article aims to initiate a critical dialogue on the impact of big data and AI in health care in order to allow for more robust evaluation of these technologies and to aid in the development of approaches to clinical care that better serve clinicians and their patients.

Clinical judgement is a central and longstanding issue in the philosophy of medicine which has generated significant interest over the past few decades. In this article, we explore different approaches to clinical judgement articulated in the literature, focusing in particular on data-driven, mathematical approaches which we contrast with narrative, virtue-based approaches to clinical reasoning. We discuss the tension between these different clinical epistemologies and further explore the implications of big data and machine learning for a philosophy of clinical judgement. We argue for a pluralistic, integrative approach, and demonstrate how narrative, virtue-based clinical reasoning will remain indispensable in an era of big data and predictive analytics., (© 2017 John Wiley & Sons, Ltd.)

Naturalistic theories of disease appeal to concepts of biological function, and use the notion of dysfunction as the basis of their definitions. Debates in the philosophy of biology demonstrate how attributing functions in organisms and establishing the function-dysfunction distinction is by no means straightforward. This problematization of functional ascription has undermined naturalistic theories and led some authors to abandon the concept of dysfunction, favoring instead definitions based in normative criteria or phenomenological approaches. Although this work has enhanced our understanding of disease and illness, we need not necessarily abandon naturalistic concepts of function and dysfunction in the disease debate. This article attempts to move towards a new naturalistic theory of disease that overcomes the limitations of previous definitions and offers advantages in the clinical setting. Our approach involves a re-evaluation of concepts of biological function employed by naturalistic theories. Drawing on recent insights from the philosophy of biology, we develop a contextual and evaluative account of function that is better suited to clinical medicine and remains consistent with contemporary naturalism. We also show how an updated naturalistic view shares important affinities with normativist and phenomenological positions, suggesting a possibility for consilience in the disease debate.

Background: Polycythemia is the most common adverse effect of testosterone replacement therapy (TRT) and may predispose patients to adverse vascular events. Current Canadian guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% (hemoglobin ≥180 g/L). This threshold has been interpreted by some physicians and patients to indicate the need for phlebotomy or blood donation while on TRT., Study Design and Methods: We reviewed all male blood donors in Southwestern Ontario at Canadian Blood Services from December 2013 to March 2016 who self-identified or were found on donor screening to be on TRT. Hemoglobin concentration was measured at the time of donation or clinic visit and with each subsequent appointment in repeat donors., Results: We identified 39 patients on TRT who presented for blood donation over a 2-year period. The mean hemoglobin level at all clinic visits was 173 g/L (range, 134-205 g/L; n = 108). Hemoglobin concentrations of 180 g/L or more (calculated hematocrit, ≥54%) were measured at 25% of appointments. Of the 27 repeat donors, 12 (44%) had persistently elevated hemoglobin levels (≥180 g/L) at subsequent donations., Conclusion: Hemoglobin concentrations were elevated in donors on TRT, and significant numbers had hemoglobin levels above those recommended by current guidelines. These data also suggest that repeat blood donation was insufficient to maintain a hematocrit below 54%. Our findings raise concerns about the persistent risk of vascular events in these donors, particularly when coupled with the misperception by patients and health care providers that donation has reduced or eliminated the risks of TRT-induced polycythemia., (© 2017 AABB.)

This essay is a reflection on the doctor-patient relationship from the perspective of two medical students, which draws on the ideas of 20th-century philosopher Martin Buber. Although Buber never wrote about medicine directly, his 'philosophy of dialogue' raises fundamental questions about how human beings relate to one another, and can thus offer valuable insights into the nature of the clinical encounter. We argue that Buber's basic word pairs, 'I-You' and 'I-It', provide a useful heuristic for understanding different modes of caring for patients, which we illustrate using examples of illness narratives from two literary works: Tolstoy's Ivan Ilych and Margaret Edson's Wit Our essay demonstrates how the humanities in general and philosophy in particular can inform a more humanistic practice for healthcare trainees and practicing clinicians alike., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231,MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior., (Copyright © 2014 Neoplasia Press, Inc. All rights reserved.)