The relationship between body composition and left ventricular performance in women with breast, lymphoma, or sarcoma cancer.

BACKGROUND: To understand how body composition in those with elevated body mass index impacts left ventricular function decline during cancer treatment, we determined the association between baseline body mass index (BMI), intra-abdominal adipose tissue (IAT) and subcutaneous adipose tissue (SAT) with baseline to 3-month left ventricular ejection fraction (LVEF) change among women receiving potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or sarcoma. METHODS: Women underwent potentially cardiotoxic chemotherapy, such as doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab, for treatment of breast cancer, lymphoma, or sarcoma. We obtained magnetic resonance images (MRIs) of body composition and cardiac function prior to treatment, and then a repeat MRI for cardiac function assessment at three months into treatment. Analyses and assessment of abdominal adipose tissue volumes and LVEF outcomes were conducted by independent reviewers blinded to all patient identifiers. A general linear model was created to examine associations between adipose tissue depots, BMI, and 3-month LVEF change. RESULTS: Women (n = 210) aged 56 ± 11 years with breast cancer, lymphoma, and sarcoma were enrolled (n = 195, 14, 1 respectively). Baseline BMI, IAT, and SAT fat were independently associated with 3-month LVEF declines (p = 0.001 to 0.025 for all). After adjusting for baseline cardiovascular disease risk factors, BMI, IAT, and SAT, BMI remained the only variable associated with 3-month LVEF decline (p = 0.047). CONCLUSIONS: These results suggest that factors other than abdominal adipose tissue or traditional cardiovascular risk factors may contribute to 3-month declines in LVEF among women with elevated BMI receiving potentially cardiotoxic chemotherapy. Further investigation should be conducted on psychosocial stress, physical activity, sleep, or diet. TRIAL REGISTRATION: DETECTIV_NCT01719562, WF99112, & WF97415-NCT02791581.

Hypertension Severity and Declines in Left Ventricular Ejection Fraction Among Women Receiving Adjuvant Chemotherapy for Breast Cancer (WF-97415 UPBEAT).

BACKGROUND: Hypertension is a risk factor for experiencing left ventricular ejection fraction (LVEF) declines during receipt of potentially cardiotoxic breast cancer (BC) treatment. We sought to determine whether the hypertension stage is associated with LVEF decline during BC treatment. METHODS: Across 24 centers, cardiac magnetic resonance measures of LVEF and brachial arterial blood pressure (BP) measurements were performed in women with stages I to III BC before and 3 months after initiating potentially cardiotoxic chemotherapy. Using multivariable analysis, we assessed in a blinded fashion the association between 3-month ΔLVEF and precancer treatment American Heart Association/American College of Cardiology stages of hypertension. RESULTS: Among 204 women, age averaged 56±1 years with 75% being White and 20% of Black race. Participants received anthracycline (45.6%), trastuzumab (22.5%), cyclophosphamide (52.9%), or paclitaxel (50%). After accounting for pretreatment LVEF, diabetes status, tobacco use, age, the number of antihypertensive medications, and body mass index, those with stage II hypertension experienced an LVEF decline of -2.89% ([95% CI, -0.69% to -5.19%]; P=0.01) relative to individuals with normal BP. Other stages saw nonsignificant declines relative to normal BP to elevated BP (-1.63% [95% CI, -0.62% to 3.88%]; P=0.16) and stage I hypertension (-0.94% [95% CI, -0.90% to 2.78%]; P=0.32). CONCLUSIONS: Compared with women receiving treatment for BC with normal BP, there is a stronger association of decline in LVEF in women with stage II hypertension relative to women with other hypertension stages. This raises the possibility that stage along with hypertension presence may be associated with an increased risk for the LVEF decline among women receiving potentially cardiotoxic chemotherapy for BC. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02791581 and NCT01719562.

Impact of COVID-19 on American Family Physicians' Intent to Retreat from Clinical Care.

PURPOSE: This survey evaluated whether the COVID-19 pandemic was a traumatic stress event for family physicians associated with burnout, changes in life priorities, and intentions to retreat from clinical practice. METHODS: We report on 683 clinically active family physicians surveyed through the Council of Academic Family Medicine's Educational Research Alliance (CERA) in the fall of 2021. RESULTS: Overall, 35.2% of family physicians experienced the pandemic as a traumatic stress like event. This was associated with changing life priorities (OR 2.6, CI 1.8-3.9), burnout (OR 1.6, CI 1.1 to 2.4), and withdrawal from clinical practice in various ways. Those who changed their priorities in life were more likely to restrict scope of practice (OR 3.9, CI 2.6-5.9), reduce clinical work effort (OR 3.4, 2.3 to 5.1), relocate (OR 3.1, CI 2.0 to 4.8), retire (OR 2.7, CI 1.4-4.9), reroute their career away from patient care (OR 2.1, CI 1.4-3.1) and less likely to avoid redesigning the practice to improve well-being (OR 0.3, CI 0.2-0.7). Those who experienced burnout were more likely to retire (OR 5.5, CI 2.8 to 10.5), reduce clinical work effort (OR 4.2, CI 2.9-6.1), reroute their career away from patient care (OR 3.9, CI 2.6-5.8), relocate (OR 3.8, CI 2.4 to 5.9), and restrict scope of practice (OR 3.3, CI 2.3 to 4.9). Overall, 48.5% of family physicians expressed some intention to retreat from clinical practice. CONCLUSION: The COVID-19 pandemic impacted family physician's career plans. Remedying burnout is a high-yield opportunity for retaining clinically active family physicians. Physicians retreating from clinical medicine related to changing life's priorities needs further exploration.

Burnout and Disengagement in Pathology: A Prepandemic Survey of Pathologists and Laboratory Professionals.

CONTEXT.­: Despite widely prevalent burnout and attendant disengagement in medicine, the specific patterns and drivers within pathology and laboratory medicine are uncommonly studied. OBJECTIVE.­: To assess the prevalence and drivers of burnout among pathology and laboratory medicine professionals, retrospectively, prior to the COVID-19 pandemic. DESIGN.­: This was a cross-sectional, mixed-methods study engaging pathology and laboratory medicine professionals as subjects. RESULTS.­: Of 2363 respondents, 438 identified as pathologists, 111 as pathology assistants, and 911 as pathology and laboratory professionals. The burnout rate was 58.4% (1380 of 2363) across all respondents in pathology and laboratory medicine. Burnout varied by job role (P < .01) and was highest among pathology and laboratory professionals. Disparities in burnout rate were observed by race. Fifty-six percent (1323 of 2363) of respondents felt that they had at least 1 symptom of burnout and were advancing toward a breaking point. Underlying factors ranked highly among all groups included control over workload and loss of meaning in work. CONCLUSIONS.­: Data provided from this cohort may help departments create successful strategies to reduce disengagement and burnout in the laboratory, especially during periods of increased stress as experienced during the COVID-19 pandemic. Further, these data may serve as a baseline comparison for future studies.

COVID-19 Traumatic Disaster Appraisal and Stress Symptoms Among Health Care Workers: Insights From the Yale Stress Self-assessment.

OBJECTIVE: To determine to what extent did health care workers experience the pandemic as a severe stress event. METHODS: This cross-sectional evaluation of 8299 health care workers, representing a 22% response rate, utilized machine learning to predict high levels of escalating stress based on demographics and known predictors for adverse psychological outcomes after trauma. RESULTS: A third of health care workers experienced the pandemic as a potentially traumatic stress event; a greater proportion of health care workers experienced high levels of escalating stress. Predictive factors included sense of control, ability to manage work-life demands, guilt or shame, age, and level of education. Gender was no longer predictive after controlling for other factors. Escalating stress was especially high among nonclinical academics and clinical private practitioners. CONCLUSION: Findings suggest adverse effects on total worker health, care quality, professionalism, retention, and acute and chronic mental health.

CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk.

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor (GPCR) for CCL22, CCR4, via impaired ß-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a unique mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased GPCR signaling and dysregulation of microenvironmental crosstalk.

Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias.

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells, is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T-LGL and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole-genome sequencing to identify mutations unique to NK-LGL leukemia. The results were analyzed to develop a resequencing panel that was applied to 58 patients. Phosphatidylinositol 3-kinase pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively. TET2 was exceptional in that mutations were present in 16 (28%) of 58 patient samples, with evidence that TET2 mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing revealed that methylation patterns were significantly altered in TET2 mutant samples. The promoter of TET2 and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3 were observed in 19 (33%) of 58 patient samples, 7 of which had concurrent TET2 mutations. Thrombocytopenia and resistance to immunosuppressive agents were uniquely observed in those patients with only TET2 mutation (Games-Howell post hoc test, P = .0074; Fisher's exact test, P = .00466). Patients with STAT3 mutation, inclusive of those with TET2 comutation, had lower hematocrit, hemoglobin, and absolute neutrophil count compared with STAT3 wild-type patients (Welch's t test, P ≤ .015). We present the discovery of TET2 mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.

Mobilizing an institutional supportive response for healthcare workers and other staff in the context of COVID-19: The Yale experience.

The burden of the COVID-19 pandemic upon healthcare workers necessitates a systematic effort to support their resilience. This article describes the Yale University and Yale New Haven Health System effort to unite several independent initiatives into a coherent integrated model for institutional support for healthcare workers. Here, we highlight both opportunities and challenges faced in attempting to support healthcare workers during this pandemic.

Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations.

Large granular lymphocyte (LGL) leukemia is a rare hematological disorder with expansion of the T-cell or natural killer (NK) cell lineage. Signal transducer and activator of transcription 3 (STAT3) exhibits somatic activating mutations in 30%-40% of LGL leukemia cases. Transcriptional targets of STAT3 include inflammatory cytokines, thus previous studies have measured cytokine levels of LGL leukemia patients compared to normal donors. Sphingolipid metabolism is a growing area of cancer research, with efforts focused on drug discovery. To date, no studies have examined serum sphingolipids in LGL leukemia patients, and only one study compared a subset of cytokines between the T-LGL and NK-LGL subtypes. Therefore, here, we included both LGL leukemia subtypes with the goals of (a) measuring serum sphingolipids for the first time, (b) measuring cytokines to find distinctions between the subtypes, and (c) establishing relationships with STAT3 mutations and clinical data. The serum analyses identified cytokines (EGF, IP-10, G-CSF) and sphingolipids (SMC22, SMC24, SMC20, LysoSM) significantly different in the LGL leukemia group compared to normal donors. In a mixed STAT3 mutation group, D661Y samples exhibited the highest mean corpuscular volume (MCV) values. We explored this further by expanding the cohort to include larger groups of single STAT3 mutations. Male D661Y STAT3 samples had lower Hgb and higher MCV compared to wild type (WT) or Y640F counterparts. This is the first report examining large groups of individual STAT3 mutations. Overall, our results revealed novel serum biomarkers and evidence that D661Y mutation may show different clinical manifestation compared to WT or Y640F STAT3.

Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia.

PURPOSE OF REVIEW: The past decade in LGL leukemia research has seen increased pairing of clinical data with molecular markers, shedding new insights on LGL leukemia pathogenesis and heterogeneity. This review summarizes the current standard of care of LGL leukemia, updates from clinical trials, and our congruent improved understanding of LGL pathogenesis. RECENT FINDINGS: Various clinical reports have identified associations between stem, bone marrow, and solid organ transplants and incidence of LGL leukemia. There is also a potential for underdiagnosis of LGL leukemia within the rheumatoid arthritis patient population, emphasizing our need for continued study. Preliminary results from the BNZ-1 clinical trial, which targets IL-15 along with IL-2 and IL-9 signaling pathways, show some evidence of clinical response. With advances in our understanding of LGL pathogenesis from both the bench and the clinic, exciting avenues for investigations lie ahead for LGL leukemia.

Organizational strategies to reduce physician burnout and improve professional fulfillment.

Burnout is highly prevalent among physicians and has been associated with negative outcomes for physicians, patients, staff, and health-care organizations. Reducing physician burnout and increasing physician well-being is a priority. Systematic reviews suggest that organization-based interventions are more effective in reducing physician burnout than interventions targeted at individual physicians. This consensus review by leaders in the field across multiple institutions presents emerging trends and exemplary evidence-based strategies to improve professional fulfillment and reduce physician burnout using Stanford's tripartite model of physician professional fulfillment as an organizing framework: practice efficiency, culture, and personal resilience to support physician well-being. These strategies include leadership traits, latitude of control and autonomy, collegiality, diversity, teamwork, top-of-license workflows, electronic health record (EHR) usability, peer support, confidential mental health services, work-life integration and reducing barriers to practicing a healthy lifestyle. The review concludes with evidence-based recommendations on establishing an effective physician wellness program.

Genomics of LGL leukemia and select other rare leukemia/lymphomas.

Genomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and when found the underlying pathway may not be attractive to drug development since so few individuals are affected. In this case, it can be useful to identify common mutational overlap among subsets of rare leukemias to increase the number of individuals that may benefit from a targeted therapy. This chapter examines the current mutational landscape of large granular lymphocyte (LGL) leukemia with a focus on STAT3 mutations, the most common mutation in LGL leukemia to date. We examined the linkage between these mutations and autoimmune symptoms and disorders, in cases of obvious and suspected LGL leukemia. We then summarized and compared mutations in a set of other rare leukemias that also have JAK/STAT signaling pathway activation brought about by genomic changes. These include T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), select peripheral T-cell lymphoma (PTCL), and adult T-cell leukemia/lymphoma (ATLL). Though STAT3 activation is common in these leukemias, the way in which it is achieved, such as the activating cytokine pathway and/or the co-mutational background, is quite diverse.

Cross-sectional survey of workplace stressors associated with physician burnout measured by the Mini-Z and the Maslach Burnout Inventory.

Rising physician burnout has adverse effects on healthcare. This study aimed to identify remediable stressors associated with burnout using the 10-item Mini-Z and the Maslach Burnout Inventory (MBI), and to compare performance of the Mini-Z's single-item burnout metric against the 22-item MBI. Surveys were emailed to 4,118 clinicians affiliated with an academic health system; 1,252 clicked the link, and 557 responded (completion rate 44%). Four hundred seventy-five practicing physicians were included: academic faculty (372), hospital employed (52), and private practitioners (81). Prevalence of burnout via the MBI was 56.6%. Predictors of burnout were poor control over workload [OR = 8.24, 95% CI 4.(81, 14.11)], inefficient teamwork [OR = 7.61, 95% (CI 3.28, 17.67)], insufficient documentation time [OR = 5.83, 95% (CI 3.35, 10.15)], hectic-chaotic work atmosphere [OR = 3.49, 95% (CI 2.12, 5.74)], lack of value-alignment with leadership [OR = 3.27, 95% (CI 2.12, 5.74)], and excessive electronic medical record time at home [OR = 1.99, 95% CI (1.21, 3.27)]. Academic faculty experienced more burnout than private practitioners (59.9% vs. 42.0%, p = 0.013). Odds of burnout associated with stressors were generally concordant via Mini-Z's burnout metric versus the MBI. The Mini-Z is a brief, valid method to identify stressors associated with burnout and guide interventions.

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes.

Calcitriol, the active form of vitamin D, has been well documented to act directly on immune cells and malignant cells. Activated T cells are one of the best characterized targets of calcitriol, with effects including decreasing inflammatory cytokine output and promoting anti-inflammatory cytokine production. However, the effects of calcitriol on natural killer (NK) cells are less clear. Reports suggest that only immature NK cell populations are affected by calcitriol treatment resulting in impaired cytotoxic function and cytokine production, while mature NK cells may have little or no response. NK cell large granular lymphocyte leukemia (NK-LGLL) is a rare leukemia with CD3-CD16+CD56+NK cell clonal expansion. The current standard treatments are immunosuppressant therapies, which are not curative. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway is hyperactivated in LGLL and is one pathway of interest in new drug target investigations. We previously demonstrated the ability of calcitriol to decrease STAT1 tyrosine 701 (p-STAT1) and STAT3 tyrosine 705 (p-STAT3) phosphorylation as well as inflammatory cytokine output of T cell large granular lymphocyte leukemia cells, but did not determine the effects of calcitriol on NK-LGLL. Therefore, in the present study, we investigated whether NKL cells, a model of NK-LGLL, and NK-LGLL patient peripheral blood mononuclear cells (PBMCs) are susceptible to treatment with calcitriol or seocalcitol (EB1089), a potent analog of calcitriol. NKL cells are dependent on interleukin (IL)-2 for survival and we show here for the first time that treatment with IL-2 induced tyrosine phosphorylation of STATs 1 through 6. Both calcitriol and EB1089 caused significant upregulation of the vitamin D receptor (VDR). IL-2 induction of p-STAT1 and p-STAT3 phosphorylation was significantly decreased after calcitriol or EB1089 treatment. Additionally, IL-10, interferon (IFN)-γ, and FMS-like tyrosine kinase 3 ligand (Flt-3L) extracellular output was significantly decreased at 100 nM EB1089 and intracellular IL-10 was decreased with either calcitriol or EB1089 treatment. We treated NK-LGLL patient PBMCs with calcitriol or EB1089 and found decreased p-STAT1 and p-STAT3 while VDR increased, which matched the NKL cell line data. We then measured 75 serum cytokines in NK-LGLL patients (n = 8) vs. age- and sex-matched normal healthy donors (n = 8), which is the first serum cytokine study for this LGLL subtype. We identified 15 cytokines, including IL-10 and Flt-3L, which were significantly different between normal donors and NK-LGLL patients. Overall, our results suggest that activating the vitamin D pathway could be a mechanism to decrease STAT1 and 3 activation and inflammatory cytokine output in NK-LGLL patients.