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Robyn M Emanuel,1 Holly L Geyer,1 Ruben A Mesa2 1Department of Internal Medicine, 2Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA Abstract: Essential thrombocythemia, polycythemia vera, and myelofibrosis belong to the class of Bcr-Abl negative hematologic neoplasms, which arise in part from varying Janus kinase-2 (JAK2) cellular deregulation. With the development of novel tyrosine kinase inhibitors capable of successfully inhibiting JAK in vivo, an influx of JAK2 inhibitors has come under clinical investigation. Ruxolitinib (Jakafi®; Incyte Corporation, Wilmington, DE, USA) was the first of these compounds to gain US Food and Drug Administration approval in late 2011 for the treatment of intermediate- and high-risk myelofibrosis. Two Phase III clinical trials – Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I and -II (COMFORT-I and -II) – played key roles in the US Food and Drug Administration approval of ruxolitinib with successful demonstration of spleen reduction and symptom palliation. Well tolerated in most patients, common side effects include cytopenias and gastrointestinal toxicities. The majority of preliminary data appears to suggest that if administered in a dose-titrated fashion, ruxolitinib can be used safely in a clinical practice setting. Additionally, patients most likely to benefit from ruxolitinib treatment are those with moderate to severe constitutional symptoms or splenomegaly. Future studies are ongoing in applying ruxolitinib to other hematologic and solid tumor malignancies. More clinical experience is recommended before the utility of this medication in a routine clinical practice setting can be fully determined. Keywords: myeloproliferative neoplasms, myelofibrosis, ruxolitinib, JAK2 inhibitors, INCB018424

Objective: The Coronavirus Disease-19 (COVID-19) pandemic caused a decline in hospitalist wellness. The COVID-19 pandemic has evolved, and new outbreaks (i.e. Mpox) have challenged healthcare systems. The objective of the study was to assess changes in hospitalist wellness and guide interventions., Methods: We surveyed hospitalists (physicians and advanced practice providers [APPs]), in May 2021 and September 2022, at a healthcare system's 16 hospitals in four US states using PROMIS® measures for global well-being, anxiety, social isolation, and emotional support. We compared wellness score between survey periods; in the September 2022 survey, we compared wellness scores between APPs and physicians and evaluated the associations of demographic and hospital characteristics with wellness using logistic (global well-being) and linear (anxiety, social isolation, emotional support) regression models., Results: In May 2021 vs. September 2022, respondents showed no statistical difference in top global well-being for mental health (68.4% vs. 57.4%) and social activities and relationships (43.8% vs. 44.3%), anxiety (mean difference: +0.8), social isolation (mean difference: +0.5), and emotional support (mean difference: -1.0) (all, p  ≥ 0.05). In September 2022, in logistic regression models, APPs, compared with physicians, had lower odds for top (excellent or very good) global well-being mental health (odds ratio [95% CI], 0.31 [0.13-0.76]; p  < 0.05). In linear regression models, age <40 vs. ≥40 years was associated with higher anxiety (estimate ± standard error, 2.43 ± 1.05; p  < 0.05), and concern about contracting COVID-19 at work was associated with higher anxiety (3.74 ± 1.10; p  < 0.01) and social isolation (3.82 ± 1.21; p  < 0.01). None of the characteristics showed association with change in emotional support. In September 2022, there was low concern for contracting Mpox in the community (4.6%) or at work (10.0%)., Conclusion: In hospitalists, concern about contracting COVID-19 at work was associated with higher anxiety and social isolation. The unchanged wellness scores between survey periods identified opportunities for intervention. Mpox had apparently minor impact on wellness.

Purpose: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms., Patients and Methods: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response., Results: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2 V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2 V617F stem/progenitor cells. ASXL 1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported., Conclusion: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection against symptomatic infection after vaccination with mRNA-1273. We fit conditional logistic regression (CLR) models stratified on residential county and calendar date of SARS-CoV-2 PCR testing to assess the association between the time elapsed since vaccination and the odds of symptomatic infection, adjusted for several covariates. There were 2,364 symptomatic individuals who had a positive SARS-CoV-2 PCR test after full vaccination with mRNA-1273 ("cases") and 12,949 symptomatic individuals who contributed 15,087 negative tests after full vaccination ("controls"). The odds of symptomatic infection were significantly higher 250 days after full vaccination compared to the date of full vaccination (Odds Ratio [OR]: 2.47, 95% confidence interval [CI]: 1.19-5.13). The odds of non-COVID-19 associated hospitalization and non-COVID-19 pneumonia (negative control outcomes) remained relatively stable over the same time interval (Day 250 OR Non-COVID Hospitalization : 0.68, 95% CI: 0.47-1.0; Day 250 OR Non-COVID Pneumonia : 1.11, 95% CI: 0.24-5.2). The odds of symptomatic infection remained significantly lower almost 300 days after the first mRNA-1273 dose as compared to 4 days after the first dose, when immune protection approximates the unvaccinated state (OR: 0.26, 95% CI: 0.17-0.39). Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. In summary, mRNA-1273 robustly protected against symptomatic SARS-CoV-2 infection at least 8 months after full vaccination, but the degree of protection waned over this time period., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Objectives: Hospitalists, comprising PAs, NPs, and physicians, manage patients hospitalized with COVID-19. To guide the development of support programs, this study compared the psychologic wellness of hospitalist PAs, NPs, and physicians during the COVID-19 pandemic., Methods: We surveyed hospitalists in 16 hospitals at Mayo Clinic, from May 4 to 25, 2020. We used PROMIS surveys for self-reported global well-being (two single-item measures), anxiety, social isolation, and emotional support, before and during the pandemic. Linear and logistic regression models were adjusted for personal and professional factors., Results: The response rate was 52.2% (N = 154/295). In adjusted linear regression models, the change in scores (before minus during pandemic) for anxiety, social isolation, and emotional support was similar for PAs and NPs compared with physicians. In adjusted logistic regression models, physicians, compared with PAs and NPs, had a higher odds of top global well-being for mental health (adjusted odds ratio [95% confidence interval]: 2.82 [1.12, 7.13]; P = .03) and top global well-being for social activities and relationships (adjusted odds ratio 4.08 [1.38, 12.08]; P = .01)., Conclusions: During the COVID-19 pandemic, global well-being was lower for PAs and NPs compared with physician hospitalists. These results can guide support programs for hospitalists., (Copyright © 2022 American Academy of Physician Associates.)

Background: The early phase of the coronavirus disease 2019 (COVID-19) pandemic had a negative impact on the wellness of hospitalists and hospital medicine advanced practice providers (APPs). However, the burden of the pandemic has evolved and the change in hospitalist and hospital medicine APP wellness is unknown., Objective: To evaluate the longitudinal trend in wellness of hospitalists and hospital medicine APPs during the COVID-19 pandemic and guide wellness interventions., Design, Setting and Participants: Between May 4, 2020, and June 6, 2021, we administered three surveys to Internal Medicine hospitalists (physicians) and hospital medicine APPs (nurse practitioners and physician assistants) at 16 Mayo Clinic hospitals in four U.S. states., Measurements: We evaluated the association of hospitalist and hospital medicine APP characteristics with PROMIS® measures of global wellbeing-mental health, global wellbeing-social activities and relationships, anxiety, social isolation, and emotional support, using logistic and linear regression models., Results: The response rates were 52.2% (n=154/295; May 2020), 37.1% (n=111/299; October 2020) and 35.5% (n=114/321; May 2021). In mixed models that included hospitalist and hospital medicine APP characteristics and survey period, APPs, compared with physicians, had lower odds of top global wellbeing-social activities and relationships (adjusted odds ratio 0.42 [0.22-0.82]; p = .01), whereas survey period showed no association. The survey period showed an independent association with higher anxiety (May 2020 vs. others) and higher social isolation (October 2020 vs. others), whereas profession showed no association. Concern about contracting COVID-19 at work was significantly associated with lower odds of top global wellbeing-mental health and global wellbeing-social activities and relationships, and with higher anxiety and social isolation. Hospitalist and hospital medicine APP characteristics showed no association with levels of emotional support., Conclusions: In this longitudinal assessment of hospitalists and hospital medicine APPs, concern about contracting COVID-19 at work remained a determinant of wellness. The trend for global wellbeing, anxiety, and social isolation may guide wellness interventions., (© 2022 Society of Hospital Medicine.)

Importance: Recent reports on waning of COVID-19 vaccine-induced immunity have led to the approval and rollout of additional doses and booster vaccinations. Individuals at increased risk of SARS-CoV-2 infection are receiving additional vaccine doses in addition to the regimen that was tested in clinical trials. Risks and adverse event profiles associated with additional vaccine doses are currently not well understood., Objective: To evaluate the safety of third-dose vaccination with US Food and Drug Administration (FDA)-approved COVID-19 mRNA vaccines., Design, Setting, and Participants: This cohort study was conducted using electronic health record (EHR) data from December 2020 to October 2021 from the multistate Mayo Clinic Enterprise. Participants included all 47 999 individuals receiving 3-dose COVID-19 mRNA vaccines within the study setting who met study inclusion criteria. Participants were divided into 2 cohorts by vaccine brand administered and served as their own control groups, with no comparison made between cohorts. Data were analyzed from September through November 2021., Exposures: Three doses of an FDA-authorized COVID-19 mRNA vaccine, BNT162b2 or mRNA-1273., Main Outcomes and Measures: Vaccine-associated adverse events were assessed via EHR report. Adverse event risk was quantified using the percentage of study participants who reported the adverse event within 14 days after each vaccine dose and during a 14-day control period, immediately preceding the first vaccine dose., Results: Among 47 999 individuals who received 3-dose COVID-19 mRNA vaccines, 38 094 individuals (21 835 [57.3%] women; median [IQR] age, 67.4 [52.5-76.5] years) received BNT162b2 (79.4%) and 9905 individuals (5099 [51.5%] women; median [IQR] age, 67.7 [59.5-73.9] years) received mRNA-1273 (20.6%). Reporting of severe adverse events remained low after the third vaccine dose, with rates of pericarditis (0.01%; 95% CI, 0%-0.02%), anaphylaxis (0%; 95% CI, 0%-0.01%), myocarditis (0%; 95% CI, 0%-0.01%), and cerebral venous sinus thrombosis (no individuals) consistent with results from earlier studies. Significantly more individuals reported low-severity adverse events after the third dose compared with after the second dose, including fatigue (2360 individuals [4.92%] vs 1665 individuals [3.47%]; P < .001), lymphadenopathy (1387 individuals [2.89%] vs 995 individuals [2.07%]; P < .001), nausea (1259 individuals [2.62%] vs 979 individuals [2.04%]; P < .001), headache (1185 individuals [2.47%] vs 992 individuals [2.07%]; P < .001), arthralgia (1019 individuals [2.12%] vs 816 individuals [1.70%]; P < .001), myalgia (956 individuals [1.99%] vs 784 individuals [1.63%]; P < .001), diarrhea (817 individuals [1.70%] vs 595 individuals [1.24%]; P < .001), fever (533 individuals [1.11%] vs 391 individuals [0.81%]; P < .001), vomiting (528 individuals [1.10%] vs 385 individuals [0.80%]; P < .001), and chills (224 individuals [0.47%] vs 175 individuals [0.36%]; P = .01)., Conclusions and Relevance: This study found that although third-dose vaccination against SARS-CoV-2 infection was associated with increased reporting of low-severity adverse events, risk of severe adverse events remained comparable with risk associated with the standard 2-dose regime. These findings suggest the safety of third vaccination doses in individuals who were eligible for booster vaccination at the time of this study.

Background: mRNA coronavirus disease 2019 (COVID-19) vaccines are safe and effective, but increasing reports of breakthrough infections highlight the need to vigilantly monitor and compare the effectiveness of these vaccines., Methods: We retrospectively compared protection against symptomatic infection conferred by mRNA-1273 and BNT162b2 at Mayo Clinic sites from December 2020 to September 2021. We used a test-negative case-control design to estimate vaccine effectiveness (VE) and to compare the odds of symptomatic infection after full vaccination with mRNA-1273 versus BNT162b2, while adjusting for age, sex, race, ethnicity, geography, comorbidities, and calendar time of vaccination and testing., Findings: Both vaccines were highly effective over the study duration (VE mRNA-1273 : 84.1%, 95% confidence interval [CI]: 81.6%-86.2%; VE BNT162b2 : 75.6%, 95% CI: 72.2%-78.7%), but their effectiveness was reduced during July-September (VE mRNA-1273 : 75.6%, 95% CI: 70.1%-80%; VE BNT162b2 : 63.5%, 95% CI: 55.8%-69.9%) as compared to December-May (VE mRNA-1273 : 93.7%, 95% CI: 90.4%-95.9%; VE BNT162b2 : 85.7%, 95% CI: 81.4%-88.9%). Adjusted for demographic characteristics, clinical comorbidities, time of vaccination, and time of testing, the odds of experiencing a symptomatic breakthrough infection were lower after full vaccination with mRNA-1273 than with BNT162b2 (odds ratio: 0.60; 95% CI: 0.55-0.67)., Conclusions: Both mRNA-1273 and BNT162b2 strongly protect against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is imperative to continue monitoring and comparing available vaccines over time and with respect to emerging variants to inform public and global health decisions., Funding: This study was funded by nference., Competing Interests: A.P., P.J.L., E.S., M.J.M.N., J.C.O., A.J.V., and V.S. are employees of nference and have financial interests in the company. nference is collaborating or has collaborated with Moderna, Pfizer, Janssen, and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. J.C.O. receives personal fees from Elsevier and Bates College and receives small grants from nference, Inc., outside the submitted work. A.D.B. is supported by grants from NIAID (grants AI110173 and AI120698), Amfar (no. 109593), and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). A.D.B. is a paid consultant for Abbvie, Gilead, Freedom Tunnel, Pinetree Therapeutics, Primmune, Immunome, and Flambeau Diagnostics; is a paid member of the DSMB for Corvus Pharmaceuticals, Equilium, and Excision Biotherapeutics; has received fees for speaking for Reach MD and Medscape; owns equity for scientific advisory work in Zentalis and nference; and is founder and President of Splissen Therapeutics. M.D.S. received grant funding from Pfizer via Duke University for a vaccine side effect registry. J.C.O., A.V., M.D.S., J.E.G., L.L.S., H.L.G., W.K., J.H., and A.D.B. are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (© 2021 The Authors.)

Background : Hospitalists, comprised of nurse practitioners and physician assistants (collectively, advanced practice providers [APPs]) and physicians, have opportunities to counsel patients and reduce SARS-CoV-2 related coronavirus disease 2019 (COVID-19) vaccine hesitancy. However, hospitalist perspectives on the COVID-19 vaccine and potential differences between APPs and physicians are unknown. Understanding hospitalist perspectives could help to address vaccine hesitancy among patients. Methods : We conducted an online survey of hospitalists at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin from 14 December 2020 through 4 January 2021. We collected demographic information and assessed perspectives on the COVID-19 vaccine and, for comparison, on the influenza vaccine. Descriptive statistics were used to compare responses between APPs and physicians. Results : The overall response rate was 42.7% (n = 128/300) and comprised of 53.9% women (n = 69/128) and 41.4% APPs (n = 53/128). Most hospitalists reported receiving or planning to receive vaccination against COVID-19 (93.7%; n = 119/128) and influenza (97.7%; n = 125/128). Most hospitalists reported they would advise 100% of patients to receive the COVID-19 vaccine (66% for APPs; 74.7% for physicians) and influenza vaccine (83% for APPs; 80% for physicians). Barriers to recommending the COVID-19 vaccine included patient health status and vaccine safety profile. Hospitalists reported that patients and coworkers receiving the COVID-19 vaccine would reduce their anxiety (~80% of hospitalists), social isolation (~64% of hospitalists), and improve their emotional support (~40% of hospitalists). APP and physician responses were similar. The possible reduction in social isolation was associated with higher odds of hospitalists advising all patients to receive the COVID-19 vaccine (adjusted odds ratio 2.95 [95% confidence interval, 1.32-6.59]; P < .008), whereas hospitalist age, gender, and profession showed no association. Conclusion : Most hospitalists would reportedly advise patients to receive the COVID-19 vaccine. Barriers to this recommendation included patient health status and vaccine safety. Hospitalists are an important resource to provide patient education and reduce COVID-19 vaccine hesitancy.

Background: Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients' opinions on smoking., Methods: A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form., Results: Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis., Conclusion: The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

Background: The Parkinson's disease (PD) patient population, with an already reduced life expectancy, is rendered particularly vulnerable by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)., Objectives: We determined the risk factors that increase the risk of death in patients with Parkinson's disease who are infected by SARS-CoV-2., Methods: Patients with a diagnosis of PD admitted to Montefiore Hospital (Bronx, New York) and tested for SARS-CoV-2 were identified. Retrospective review of electronic medical records confirmed the diagnosis; patients were classified by severity of PD. PD severity, demographic, socioeconomic factors, and co-morbidities were correlated with mortality rates in patients with SARS-CoV-2., Results: We identified 162 patients meeting criteria; chart review confirmed a diagnosis of PD in 70 patients. Of the 70 patients, 53 were positive for SARS-CoV-2 and 17 were negative. PD patients with SARS-CoV-2 infection had a higher mortality rate (35.8%) compared to PD patients without the infection (5.9%, P  = 0.028). PD patients older than 70 years of age, those with advanced Parkinson's disease, those with reductions in their medications, and non-Hispanics (largely comprised of Black/African- Americans) had a statistically significant higher mortality rate, if infected., Conclusions: PD did not increase mortality rates from SARS-CoV-2 infection when age was controlled. However, certain unalterable factors (advanced disease and age greater than 70 years) and alterable ones (reductions in PD medications) placed PD patients at increased risk for mortality. Also several socioeconomic factors contributed to mortality, for example, non-Hispanic patients with SARS-CoV-2 infection fared worse, likely driven by poorer outcomes in the Black/African-American cohort., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: To estimate the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in health care personnel., Methods: The Mayo Clinic Serology Screening Program was created to provide a voluntary, two-stage testing program for SARS-CoV-2 antibodies to health care personnel. The first stage used a dried blood spot screening test initiated on June 15, 2020. Those participants identified as reactive were advised to have confirmatory testing via a venipuncture. Venipuncture results through August 8, 2020, were considered. Consent and authorization for testing was required to participate in the screening program. This report, which was conducted under an institutional review board-approved protocol, only includes employees who have further authorized their records for use in research., Results: A total of 81,113 health care personnel were eligible for the program, and of these 29,606 participated in the screening program. A total of 4284 (14.5%) of the dried blood spot test results were "reactive" and warranted confirmatory testing. Confirmatory testing was completed on 4094 (95.6%) of the screen reactive with an overall seroprevalence rate of 0.60% (95% CI, 0.52% to 0.69%). Significant variation in seroprevalence was observed by region of the country and age group., Conclusion: The seroprevalence for SARS-CoV-2 antibodies through August 8, 2020, was found to be lower than previously reported in other health care organizations. There was an observation that seroprevalence may be associated with community disease burden., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Opioid prescribing occurs within almost every healthcare setting. Implementation of safe, effective opioid stewardship programs represents a critical but daunting challenge for medical leaders. This study sought to understand the barriers and aids to the routine use of clinical guidelines for opioid prescribing among healthcare professionals and to identify areas in need of additional education for prescribing providers, pharmacists, and nurses., Methods: Data collection and analysis in 2018-2019 employed a team of two trained facilitators who conducted 20 focus groups using a structured facilitation guide to explore operational, interpersonal, and patient care-related barriers to best practice adherence. Each professional group was interviewed separately, with similar care settings assigned together. Invitation to participate was based on a sampling methodology representing emergency, medical specialty, primary care, and surgical practice settings., Results: Key concerns among all groups reflected the inadequacy of available tools for staff to appropriately assess and treat patients' pain. Tools and technology to support safe opioid prescribing were also cited as a barrier by all three professional groups. All groups noted that prescribers tend to rely upon default settings within the electronic medical record when issuing prescriptions. Both pharmacists and prescribers cited time and scheduling as a barrier to adherence., Conclusions: In spite of significant regulatory and public policy efforts to address the opioid crisis, healthcare organizations face significant challenges to improve adherence to best practice prescribing guidelines. These findings highlight several facilitators for change which could boost opioid stewardship initiatives to focus on critical systems' factors for improvement.

Background: Patients with COVID-19 infection requiring in-hospital care are frequently managed by Internal Medicine hospitalists, comprised of physicians, nurse practitioners and physician assistants. There is sparse information on the psychological impact of the COVID-19 pandemic on Internal Medicine hospitalists., Methods: We surveyed Internal Medicine hospitalists at Mayo Clinic sites in four states (Arizona, Florida, Minnesota, and Wisconsin). We collected demographic information, and used Patient-Reported Outcomes Measurement Information System (PROMIS®) measures to assess global well-being, anxiety, social isolation, and emotional support. Descriptive statistics were used to compare responses between two periods: prior to the pandemic (before March 15 th , 2020), and during the pandemic (March 15 through 30 April 2020). The survey was conducted from May 4-25, 2020., Results: Of 295 Internal Medicine hospitalists, 154 (52%) responded. Fifty-six percent were women (n = 85/154) and 54% were physicians (n = 84/154). Most hospitalists (75%; n = 115/154) reported concerns about contracting COVID-19 infection at work, and 5% (n = 8/154) reported changing where they lived during the pandemic. Most hospitalists (73%; n = 112/154) reported relying primarily on institutional resources for COVID-19 information. During the pandemic, the percentage of participants with excellent or very good global well-being decreased (90% prior to pandemic vs. 53% during pandemic), with increases in mean anxiety (-4.88 [95% confidence interval, - 5.61 to - 4.16]; P <.001) and social isolation (-3.91[95% confidence interval, - 4.68 to - 3.13]; P <.001). During the same period, there was a small decrease in mean emotional support (1.46 [95% confidence interval, 0.83 to 2.09]; P <.001)., Conclusion: During the COVID-19 pandemic, Internal Medicine hospitalists reported lower global well-being, higher anxiety and social isolation, and a small decrease in emotional support. These results provide a framework to develop programs to support hospitalists and potentially mitigate long-term psychological sequelae including burnout.

Background: Physician hospitalists may participate in research and generate knowledge for evidence-based hospital practice. Despite this, physician hospitalists are primarily involved in patient care, and there is sparse information on barriers for their participation in research and if these barriers differ by career stage., Methods: We conducted a survey of physician hospitalists at Mayo Clinic sites based in four states (Arizona, Florida, Minnesota, and Wisconsin). We surveyed physician hospitalists on demographics, academic rank, current research skills, barriers for participation in research, and research skills they aspire to acquire. Responses were summarized using descriptive statistics and categorized by early-career (<10 years), mid-career (10-20 years), and later-career (≥20 years) stages at Mayo Clinic. The survey was conducted from March to April 2019., Results: Of 188 physician hospitalists, there was a 52% response rate with 71% in early career, 21% mid-career, and 7% late career, with 39% female. Physician hospitalists at early-career (90%), mid-career (76%), and later-career (71%) stages were interested in participating in research. Among physician hospitalists with ≤3 peer-reviewed publications, barriers for participation in research included lack of mentorship, time, research skills, and funding. Among physician hospitalists with ≥4 peer-reviewed publications, factors for research success included mentorship (89% early-career, 38% mid-career, 75% later-career; p = 0.002) and membership in a research team. Compared to mid- and later-career physician hospitalists, a higher proportion of early-career hospitalists was interested in acquiring skills to both critically review the literature (70% early-career, 43% mid-career, 0% later-career; p = 0.006) and write manuscripts (86% early-career, 57% mid-career, 50% later-career; p = 0.02); there was generally similar interest across career stages to acquire skills to conduct literature searches and write grants., Conclusion: The generally similar responses from physician hospitalists across career stages highlight system-level opportunities to increase research mentorship, promote the acquisition of research skills, and reduce barriers for participation in research.

Advanced practice providers and physicians at an academic healthcare system comprising more than 15 hospitals across four US states were surveyed to identify barriers to participation in research. Overall, barriers reported by advanced practice providers and physicians were more similar than different, highlighting system-level opportunities to build research skills and accelerate academic productivity.

Competing Interests: The authors have no competing interests to declare.

The field of malignant hematology has experienced extraordinary advancements with survival rates doubling for many disorders. As a result, many life-threatening conditions have since evolved into chronic medical ailments. Paralleling these advancements have been increasing rates of complex hematologic pain syndromes, present in up to 60% of patients with malignancy who are receiving active treatment and up to 33% of patients during survivorship. Opioids remain the practice cornerstone to managing malignancy-associated pain. Prevention and management of opioid-related complications have received significant national attention over the past decade, and emerging data suggest that patients with cancer are at equal if not higher risk of opioid-related complications when compared with patients without malignancy. Numerous tools and procedural practice guides are available to help facilitate safe prescribing. The recent development of cancer-specific resources directing algorithmic use of validated pain screening tools, prescription drug monitoring programs, urine drug screens, opioid use disorder risk screening instruments, and controlled substance agreements have further strengthened the framework for safe prescribing. This article, which integrates federal and organizational guidelines with known risk factors for cancer patients, offers a case-based discussion for reviewing safe opioid prescribing practices in the hematology setting., (© 2020 by The American Society of Hematology.)

The opioid crisis is a major concern of most health care institutions, including our large academic center. In this article, an organized approach to managing the epidemic institutionally is discussed. An Opioid Stewardship Program was instituted at our tertiary-care center with multiple sites and states of practice, which included diverse membership and expertise. Charges of the program included reviewing current practice, workflows, and external and internal guidelines and evaluating and standardizing prescribing practices. The development of an Opioid Stewardship Program resulted in: (1) an understanding of our diverse prescribing practices and the formation of patient- and procedure-specific guidelines to manage them, (2) education tools for our patients and providers, and (3) workflows and practice advisories within the electronic health record to support appropriate prescribing and monitoring of patients. This ongoing work continues to evolve in response to the needs of our patients, changing regulatory environments, and our improved understanding of our practices., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Patients admitted to a medical-surgical unit infrequently require early transfer to higher level care, although how their inpatient length of stay compares to untransferred patients, or those directly admitted to intermediate care, is unknown. We sought to compare the inpatient length of stay of these groups., Design: Single-site retrospective analysis., Setting: An academic hospital specializing in complex care., Patients: We evaluated 23,694 patients admitted to the Hospital Internal Medicine service over a 4-year period (January 1, 2013, to December 31, 2016)., Interventions: None., Measurements and Main Results: Using 6- and 24-hour definitions of early transfer, we categorized patients as admitted to medical-surgical unit without early transfer (medical-surgical unit), transferred (TX) early to higher level care, or initially admitted to an intermediate care unit. We report patient characteristics and inpatient length of stay adjusted for patient demographics (age and sex) and initial acuity (measured by Emergency Severity Index). There were significant increases in both unadjusted inpatient length of stay (6 hr: medical-surgical unit = 73.4 hr, TX = 137.9 hr, intermediate care unit = 101.1 hr; 24 hr: medical-surgical unit = 72.4 hr, TX = 141.9 hr, intermediate care unit = 98.2 hr; p < 0.01 for all groups) and adjusted inpatient length of stay (6-hr definition: medical-surgical unit = 50.9 hr [95% CI, 50.3-51.6 hr], TX = 100.4 hr [90.4-112.0 hr], intermediate care unit = 72.3 hr [70.6-74.0 hr]; 24-hr definition: medical-surgical unit = 50.3 hr [49.7-50.9 hr], TX = 108.3 hr [101.5-116.0 hr], intermediate care unit = 70.7 hr [69.0-72.3 hr]; p < 0.0001 for comparison of TX to medical-surgical unit and intermediate care unit in both groups). The increases in inpatient length of stay for the TX groups were not explained by differences in demographics or acuity., Conclusions: In a single facility study, patients admitted to a medical/surgical unit who require early transfer to intermediate care unit have a significant and unexplained increase in inpatient length of stay. This unexplained increased inpatient length of stay suggests that triage to the appropriate inpatient unit significantly affects inpatient length of stay., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

A 47-year-old woman presented with sicca symptoms, polyarthralgias, polymyalgias and dysphagia. She was found to have positive antinuclear, anti-SSA-Ro and anti-SSB-La antibodies. Slit lamp exam confirmed the presence of keratoconjunctivitis sicca, and the patient was diagnosed with Sjögren's syndrome. Three years later, she was referred for evaluation of gait instability associated with recent falls. On physical examination, the patient was found to have bilateral ptosis, percussion myotonia, distal upper and lower extremity weakness, and a steppage gait. Electromyography demonstrated electrical myotonia. Genetic testing revealed expanded CTG repeats (733 and 533) in the myotonic dystrophy type 1 (DM1) protein kinase gene, confirming the diagnosis of DM1. Dysphagia, pain and eye discomfort may occur in both Sjögren's syndrome and DM1, and in this case, may have delayed the diagnosis of muscular dystrophy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Administering questionnaires to patients is an efficient and effective method for assessing patients' symptoms. However, item nonresponse (skipped questions) potentially compromises the utility of these questionnaires. Using an international sample of 2,067 patients with myeloproliferative neoplasms, we evaluated the impact of item nonresponse on scoring of the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10). We characterized item nonresponse on the MPN-10 and compared strategies for addressing item nonresponse (available-case analysis, proration, and multiple imputation) on the MPN-10 (multi-symptom assessment) and Brief Fatigue Inventory (BFI; single-symptom assessment). Characteristics of multi-symptom assessments would be expected to adversely affect proration, yet proration and multiple imputation provided very similar results for both the MPN-10 and BFI. This is likely because the MPN-10 item missing data rates were low, consistent with prior clinic- and internet-based studies. These results support the published scoring method for the MPN-10 (proration).

Patients with myeloproliferative neoplasms (MPNs) experience burdensome symptoms that negatively affect their quality of life. How MPN symptoms relate with medical disability leave (MDL) among patients with the disease has not been previously examined. Using data collected from the Living with MPNs patient survey, symptom burden and functional status were compared in patients who reported taking MDL due to their MPN versus patients who reported no changes in employment status. Among 592 patients who were employed full- or part-time at diagnosis, 24.8% reported taking ≥ 1 MDL and 49.4% reported no change in employment status as a result of their MPN. Of the patients who took MDL, 29.9% took ≥ 2 MDLs, and most patients (62.6%) did not return to work. All 10 symptoms comprising the MPN Symptom Assessment Form were significantly more frequent and severe in patients who took MDL compared with those who had no employment change. Furthermore, functional impairments were also significantly more frequent among patients who went on MDL versus those with no employment change. Effective management of MPN-related symptoms may reduce disability leave among patients with high symptom burden.

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n=89) and without (n=329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100×10 9 /L (moderate 51-100×10 9 /L; severe ≤50×10 9 /L), was associated with anemia (76% vs. 45%, p<0.001), leukopenia (29% vs. 11%, p<0.001), and need for red blood cell transfusion (35% vs. 19%, p=0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p<0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p=0.04), leukopenia (40% vs. 20%, p=0.04), and transfusion requirements (51% vs. 20%, p=0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mycobacterium avium intracellulare infection or colonization should be considered in the differential diagnosis of hypercalcemia, especially in immunocompromised individuals, in the appropriate clinical context.

Current guidelines suggest that polycythemia vera (PV) patients maintain a strict hematocrit less than 45%. However, to date, little is known about the relationship between HCT control and PV- related symptom burden. In this study, PV patient data was analyzed from the CYTO PV trial (n = 224) and the MPN-SAF study cohort (n = 645). No significant differences in symptom burden were seen at the 6 and 12 month follow-up when evaluating prospective hematocrit control in the CYTO PV cohort. Patients in the MPN-SAF cohort with a worst item score of greater than 5/10 on the Myeloproliferative Neoplasm Symptom Total Symptom Score had a significantly lower mean hematocrit (p = .0376). These findings suggest a relationship between traditional aggressive therapy for PV and increased symptom burden with prolonged therapy. Thus, symptom burden should be considered when contemplating the choice of therapy in the second-line setting for PV.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression., (Copyright© Ferrata Storti Foundation.)

Background: Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms., Methods: A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population., Results: Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P<.001), with 64% of patients with MPN describing some degree of sexual dysfunction and 43% experiencing severe symptoms. The presence of sexual symptoms correlated closely with all domains of patient functionality (physical, social, cognitive, emotional, and role functioning) and were associated with a reduced quality of life. Sexual problems also were found to be associated with other MPN symptoms, particularly depression and nocturnal and microvascular-related symptoms. Sexual dysfunction was more severe in patients aged >65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids., Conclusions: The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016;122:1888-96. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs., Methods: A 70-item, Internet-based survey regarding fatigue was developed by MPN investigators and patients/advocates and hosted by the Mayo Clinic Survey Research Center., Results: Fatigue was found to be prevalent and severe among international survey respondents (1788 respondents). Higher body mass index (P<.001), current use of alcohol (P<.001), and current tobacco use (P = .0025) were found to be significantly associated with greater fatigue. Moderate/severe fatigue was present more frequently in those individuals who did not exercise compared with those who reported exercising at least once per week (P<.001). Medical comorbidities found to be significantly associated with greater fatigue included restless leg syndrome (P = .006), diabetes mellitus (P = .045), fibromyalgia (P < 0.001), chronic fatigue syndrome (P = .006), and chronic kidney disease (P = .02). Current use of antidepressants (P<.001), antihistamines (P = .0276), antianxiety medications (P = .0357), and prescription pain medications (P<.001) were found to be associated with worsened fatigue. Nearly 25% of respondents scored > 2 on the Patient Health Questionnaire, indicating a high probability of depression. Higher Brief Fatigue Inventory score, Myeloproliferative Neoplasm Total Symptom Score, and individual symptom items were all associated with a higher likelihood of depressive symptoms (P<.0001)., Conclusions: The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. Patients with MPNs likely have a higher prevalence of mood disturbances compared with the general population, suggesting the need to assess and intervene in this domain., (© 2015 American Cancer Society.)

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal stem cell-derived malignancies that include primary myelofibrosis, polycythemia vera and essential thrombocythemia and are characterized by dysregulated Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. Clinical manifestations include splenomegaly, cytopenias and/or systemic inflammation. Patients have a heterogeneous symptom profile that includes fatigue, loss of appetite, pruritus and night sweats, which significantly impact quality of life (QoL) and lead to poor survival outcomes. With the introduction of JAK inhibitors, improvement in disease-related symptoms has emerged as a realistic expectation of therapy and an integral measure of clinical efficacy. The JAK1/JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis and is currently under clinical development for polycythemia vera. Ruxolitinib has demonstrated significant reductions in symptom burden, with consequent improvements in QoL measures. With the potential to improve QoL, recognition of the impact and burden of symptoms on patients with MPNs is critical.

Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant disease burden composed of splenomegaly, constitutional symptoms and a reduced life expectancy. The advent of targeted treatments has provided new means by which to improve MF associated splenomegaly, symptoms, health-related quality of life and even mortality., Areas Covered: We discuss the spectrum of targeted treatments currently under investigation for MF. We furthermore compare their effects on improving anemia, reducing fibrosis and splenomegaly and enhancing symptom control., Expert Opinion: MF is a complex disorder, partly attributable to its heterogeneity. Although the severity of patient symptoms correlates with risk category, high symptom burden may also be observed in low-risk patients. Serial use of PRO tools allows clinicians to objectively evaluate the MF symptom burden, compare efficacy of therapies and adjust medications to improve symptom control. Novel targeted agents have proven superior to historic treatment regimens for symptom management. Promising treatment categories include JAK2 inhibitors, histone deacetylase inhibitors, hypomethylating agents, heat shock protein-90 inhibitors, hedgehog inhibitors, PI3-AKT-mTOR inhibitors, antifibrosing agents and telomerase inhibitors. The majority of therapies remain under investigation, either alone or in combination with other treatments. It is anticipated that these agents will be increasingly integrated into standard treatment algorithms for MF symptom management.

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal stem cell derived malignancies, which include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The MPNs are characterized by dysregulated JAK-STAT signaling pathways. PV and ET are associated with an increased risk of thrombo-hemorrhagic complications, risk of progression to MF and leukemia. Presentation of patients with PV and ET is variable and usually as a result of abnormal full blood count indices (raised hemoglobin and hematocrit, leukocytosis, and thrombocytosis). Presentation with thrombosis or splenomegaly occurs in ~30% of patients. Historically thought of as indolent compared with MF, patients with PV and ET have significant disease symptom burden which does not directly correlate to the current clinical prognostic classifications. The mainstay of therapy is reserved for patients with high-risk disease and thus excludes a population of patients with significant symptom related morbidity impacting their quality-of-life and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions such as JAK2 inhibitors and HDAC inhibitors. We will review the advances in the field of MPN symptom assessment and symptom burden experienced by ET and PV patients. We will also discuss the risk-stratified management of ET and PV patients alongside symptom assessment and the impact of potential novel therapies, for patients who fail to respond to conventional treatment., (© 2015 by The American Society of Hematology. All rights reserved.)

Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs., (© 2014 by The American Society of Hematology. All rights reserved.)

BCR-ABL-negative myeloproliferative neoplasms include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Clonal stem cell proliferation and dysregulated JAK/STAT molecular pathways characterize these hematologic malignancies. Symptoms experienced by patients are heterogeneous including excessive and disabling fatigue, early satiety, anorexia, pruritus, bone pain, night sweats, cachexia, abdominal pain and discomfort, and cognitive complaints. Patients also experience impaired quality of life along with decreased overall survival. New targeted drug therapies, including JAK2 inhibitors, have demonstrated remarkable success in alleviating the myeloproliferative neoplasm (MPN) symptomatic burden, reducing splenomegaly and improving quality of life while offering overall survival benefit. Within the USA, FDA approval has only been granted to use JAK2 inhibitors in intermediate- to high-risk myelofibrosis. However, given that low-prognostic-scoring patients have been shown to have considerable symptomology, there is a possibility that lower-risk patients may benefit from therapy. More than ever, the need for accurate MPN symptom burden assessment and subsequent addition of targeted therapies is critical in the treatment of MPNs. This article discusses the role of MPN symptom burden and quality of life as therapeutic targets in the context of recent MPN clinical advances.

Ethambutol is known to cause optic neuropathy and, more rarely, axonal polyneuropathy. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed visual loss and paresthesias after 11 weeks of exposure to a supratherapeutic dose of ethambutol. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to ethambutol toxicity.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis., (© 2014 by The American Society of Hematology.)

A 63-year-old man presented with 4 years of orthostatic tremor while standing, resolving after sitting or leaning against a wall. There was marked subjective unsteadiness, but no falls. Surface EMG in arms and legs demonstrated a 14- to 16-Hz synchronous tremor in antagonist muscles (video on the Neurology Web site at www.neurology.org.).

Introduction: Dysregulation of JAK-STAT signaling is a pathogenetic hallmark of myeloproliferative neoplasms (MPNs) arising from several distinct molecular aberrations, including mutations in JAK2, the thrombopoietin receptor (MPL), mutations in negative regulators of JAK-STAT signaling, such as lymphocyte-specific adapter protein (SH2B3), and epigenetic dysregulation as seen with Suppressor of Cytokine Signaling (SOCS) proteins. In addition, growth factor/cytokine stimulatory events activate JAK-STAT signaling independent of mutations., Areas Covered: The various mutations and molecular events activating JAK-STAT signaling in MPNs are reviewed. Detailed inhibitory kinase profiles of the currently developed JAK inhibitors are presented. Clinical trial results for currently developed JAK targeting agents are comprehensively summarized. The limitations of JAK-STAT targeting in MPNs, as well as potential rational combination therapies with JAK2 inhibitors, are discussed., Expert Opinion: Aberrant JAK-STAT signaling is an underlying theme in the pathogenesis of MPNs. While JAK2 inhibitors are active in JAK2V617F and wild-type JAK2 MPNs, JAK2V617F mutation-specific or JAK2-selective inhibitors may possess unique clinical attributes. Complimentary targeting of parallel pathways operating in MPNs may offer novel therapeutic approaches in combination with JAK inhibition. Understanding the intricacies of JAK-STAT pathway activation, including growth factor/cytokine-driven signaling, will open new avenues for therapeutic intervention at known and novel molecular vulnerabilities of MPNs.

Purpose: Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy., Patients and Methods: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers., Results: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method., Conclusion: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Historically, complex biochemical alterations defining these heterogeneously distinct malignancies have remained elusive and constrained available therapy options. The discovery of Janus kinase (JAK) mutations collectively present in BCR-ABL-negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities, as well as provided a unique platform for inhibiting symptom-directing proinflammatory cytokines. INCB018424, CYT387, SB1518, and TG101348 are among the most propitious JAK2 inhibitors under investigation, providing substantial improvement in constitutional symptoms, transfusion-dependent cytopenias, and reduction in spleen size. Despite their attributes, evidence of complete or partial remission has yet to be observed with therapy. Many uncertainties surrounding the full clinical potential of JAK2 inhibitors persist. Treatment guidelines addressing optimal stages for drug implementation, ideal dosing parameters and criteria for medication continuation/withdrawal may effectively resolve these ongoing concerns and provide advancements in the morbidity and mortality of these multifaceted disease processes.

Pomalidomide is an immunomodulatory derivative (IMiD) active in multiple myeloma. In this report, we review the course of two patients receiving pomalidomide therapy who subsequently developed dyspnea, fever, hypoxia, and ground-glass opacities on CT scan. An extensive workup for infectious causes was negative. Both patients improved with discontinuation of the medication and/or treatment with corticosteroids. Both patients were restarted on pomalidomide therapy at a lower dose, with one patient experiencing an immediate recurrence of pulmonary symptoms. The combination of symptoms, radiographic findings, clinical course, and response to treatment strongly supports the diagnosis of acute pulmonary toxicity secondary to pomalidomide. We then review previously published pulmonary toxicity data on thalidomide and lenalidomide and compare the described clinical courses, radiographic findings, and responses to treatment with those observed in our patients. We conclude that pulmonary toxicity is a potential adverse effect of pomalidomide therapy and encourage physicians to remain cognizant of its clinical presentation.

Rapid-onset dystonia-parkinsonism (RDP) is a rare condition with autosomal-dominant inheritance causing dystonia and parkinsonism which develop over a short period of time. It results from abnormalities in the Na(+)/K(+)-ATPase pump due to mutations in the ATP1A3 gene. This chapter reviews the clinical features, genetics, and diagnosis of this disorder., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Metastasis to the breast is a rare occurrence, constituting fewer than 2% of all breast tumours. Of all metastatic tumours in the breast, most arise from contralateral breast primaries. Other reported primary solid tumour sites include melanoma; lung, gastric, and renal cancers; and approximately 29 cases of carcinoid tumour.Ambiguous presentations and an absence of carcinoid syndrome features make accurate radiographic and histologic assessment of breast carcinoids challenging. Here, we report the case of a 52-year-old woman who presented with a mammographic abnormality in the left breast. Excisional biopsy revealed histopathology consistent with carcinoid. After an exhaustive work-up, carcinoid within the terminal ileum was ultimately identified, and the woman was diagnosed with metastatic breast carcinoid, an exceedingly rare entity. This paper describes the common mammographic, cytologic, and immunohistochemical features typical of metastatic breast carcinoid tumours, together with their common clinical features, prognosis, and treatment options.

Extraskeletal myxoid chondrosarcoma (EMS) is a rare oncologic phenomenon characterized by chondroid and neurogenic differentiation in extraskeletal locations. These tumours represent fewer than 2.5% of all soft-tissue sarcomas and are most commonly found in the lower extremities, limb girdles, distal extremities, and trunk. Their presence in cardiac tissue is exceedingly unusual; just a single case of ems metastatic to the heart has been reported, and no cases of primary cardiac EMS are known.Here, we report the case of a 26-year-old man who presented to his physician with a chest wall mass. Further evaluation led to the discovery of a large intracardiac mass with multiple end-organ growths. Complete work-up of this patient included cardiac biopsy, echocardiography, magnetic resonance imaging, positron-emission tomography, computed tomography, and fluorescence in situ hybridization studies for the translocation involving the EWSR1 gene locus (22q12). Results of the foregoing studies confirmed the diagnosis of ems, but the origin of this patient's tumours remains elusive and the contention between a primary cardiac source and cardiac metastasis has yet to be resolved.This article describes the histopathology, immunohistochemistry, and chromosomal aberrations common to ems, together with the common presenting features, natural history, and prognosis.

Dystonia is a movement disorder with many presentations and diverse causes. A systematic approach to dystonia helps to ensure that patients with this disorder receive optimum care. This Review begins with a summary of the clinical features of dystonia, followed by a discussion of other disorders to be considered and excluded before assigning the diagnosis of dystonia. Next, we emphasise the importance of classifying dystonia along several dimensions, and we explain how doing so aids in narrowing the differential diagnosis. The more common forms of dystonia are discussed in detail. Finally, we describe how to apply the clinical information for selection of appropriate laboratory investigations.