What is well-being? A scoping review of the conceptual and operational definitions of occupational well-being.

Well-being is a multifaceted construct that is used across disciplines to portray a state of wellness, health, and happiness. While aspects of well-being seem universal, how it is depicted in the literature has substantial variation. The aim of this scoping review was to identify conceptual and operational definitions of well-being within the field of occupational health. Broad search terms were used related to well-being and scale/assessment. Inclusion criteria were (1) peer-reviewed articles, (2) published in English, (3) included a measure of well-being in the methods and results section of the article, and (4) empirical paper. The searches resulted in 4394 articles, 3733 articles were excluded by reading the abstract, 661 articles received a full review, and 273 articles were excluded after a full review, leaving 388 articles that met our inclusion criteria and were used to extract well-being assessment information. Many studies did not define well-being or link their conceptual definition to the operational assessment tool being used. There were 158 assessments of well-being represented across studies. Results highlight the lack of a consistent definitions of well-being and standardized measurements.

Building leadership capacity among junior faculty: Evaluating multi-level outcomes of a leadership program.

Introduction: Leadership is recognized as an essential competency across healthcare and science. The LEAD (Leadership Emerging in Academic Departments) program at the Icahn School of Medicine at Mount Sinai (ISMMS) is a structured 12-month blended learning program that catalyzes personal and professional leadership skills, behaviors, and capacity. Methods: Utilizing a post-program survey design, the Leadership Program Outcome Measure (LPOM) explored self-reported impact of the LEAD program on leadership knowledge and skills in relation to personal and organizational leadership constructs. Application of leadership skills to practice was tracked via completion of a leadership-focused capstone project. Results: Over 3 cohorts, 76 participants graduated and 50 completed the LPOM survey (68% response rate). Participants self-reported an increase in leadership skills, conveyed plans to use acquired skills in current and future leadership positions, and noted improved leadership skills across the personal and organizational domains. Comparatively less change was detected at the community level. Tracking of capstone projects found that 64% of participants were able to successfully implement their project in practice. Conclusion: LEAD was successful in promoting the development of personal and organizational leadership practices. The LPOM evaluation provided a valuable lens through which to assess the individual, interpersonal, and organizational impact of a multidimensional leadership training program.

The TCI Clinical Encounter Program for PhD Students in Cancer Biology: a Feasibility Pilot.

Clinical rotations are often not included in graduate-level cancer biology curricula; however, basic insight into clinical oncology is often crucial for developing translational research that addresses unmet needs with the potential to benefit cancer patients. We describe a needs assessment, design, implementation, and descriptive evaluation of an oncology-specific pilot clinical encounter program developed for PhD students in the Cancer Biology Training Area (CAB) in the Graduate School of Biomedical Sciences (GSBS) and Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai (ISMMS). Prior to the development of this pilot program, CAB students, in years 2-5 + , were surveyed to determine their interest in a structured clinical experience. Seventeen out of thirty-one students responded (55%) to the survey. Of those seventeen respondents, fifteen (88.2%) expressed that exposure to cancer patients in the clinical setting would be useful for their pre-doctoral biomedical science and cancer biology training and indicated an interest in participating in the clinical encounter program. Based on these responses, a three-session clinical encounter pilot program was designed. Two separate cohorts of 5 students participated in this pilot program. During a formal debrief, following the clinical experience, students commented on the resilience of patients and the importance of research on clinical decision making, and reported that they found the experience motivational. Five out of 10 students responded (50%) to a post-program assessment survey; all five respondents answered that they would recommend the clinical encounter program to their peers. While limited in size and scope, this pilot TCI Clinical Encounter Program proved feasible and has the potential to enrich and inform the experience of PhD students pursing advanced degrees in a cancer biology.

Tisch Cancer Institute Scholars Program: Mentored Cancer Research Training Pipeline for Medical Students.

Cancer research has led to unprecedented advances in treatment in recent decades. Physician-scientists have played a crucial role in these advances given their unique perspective at the intersection between basic research and clinical care, though their representation in cancer research has been in progressive decline. Cancer research programs that feature strong mentorship at the medical student level are associated with increased likelihood of alumni choosing a cancer research career path. In an effort to increase the cancer research medical student training pipeline, senior research faculty from the Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai (ISMMS) developed the TCI Scholars Program, a rigorous mentored research training program funding medical students' summer research. This program is currently in its third year and has garnered significant interest among mentors and students alike from all four TCI Cancer Center Support Grant (CCSG)-funded research programs. Herein, we describe the development, implementation, evaluation, and major outcomes of this program.

Impact of rituximab on COVID-19 outcomes.

Rituximab is associated with prolonged B-cell depletion and secondary hypogammaglobulinemia and is associated with a dampened humoral response and increased infectious complications. To describe the potential impact of prior rituximab therapy on clinical outcomes from SARS-CoV-2 infection and development of COVID-19 antibodies, we conducted a retrospective study of adults across the Mount Sinai Health System diagnosed with COVID-19 who received rituximab for any indication from February 2019 to October 2020. Patients' baseline characteristics, markers of disease severity, clinical outcomes, and antibody development were examined. Of the 49 patients included in the analysis, 63.2% required hospitalization for COVID-19, 24.5% required an ICU admission, and 32.7% died. Proximity of last rituximab infusion and COVID-19 diagnosis did not affect rates of hospitalization, admission to intensive care units or death. Over half (51.7%) of those whose antibodies were checked developed neutralizing anti-spike protein antibodies. The median time between rituximab administration and COVID-19 diagnosis was not significantly different between those who developed antibodies and those who did not (p = .323). Of the 14 patients with documented negative COVID-19 antibody titers, 11 of them survived SARS-CoV-2 infection, indicating that development of neutralizing antibodies may not be necessary for recovery from COVID-19.

Tales from New York City, the pandemic epicenter: A case study of COVID-19 impact on clinical and translational research training at the Icahn School of Medicine at Mount Sinai.

In the spring of 2020, New York City was at the epicenter of the COVID-19 pandemic in the USA, resulting in disruption of TL1 and KL2-mentored Clinical and Translational Science (CTS) research at the Icahn School of Medicine at Mount Sinai (ISMMS). The impact of the pandemic on trainees' research productivity and career plans was explored using a qualitative survey. Participant responses were analyzed using coding and categorization. Six key themes emerged: redirection of effort, reduced access to people, lack of access to resources, home as a workplace, future uncertainty, and stress and anxiety. Insight into participant experiences allows for the development of support strategies and resources to address trainee needs.

Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.

Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis.

OBJECTIVE: To evaluate association between biomarkers and outcomes in COVID-19 hospitalised patients. COVID-19 pandemic has been a challenge. Biomarkers have always played an important role in clinical decision making in various infectious diseases. It is crucial to assess the role of biomarkers in evaluating severity of disease and appropriate allocation of resources. DESIGN AND SETTING: Systematic review and meta-analysis. English full text observational studies describing the laboratory findings and outcomes of COVID-19 hospitalised patients were identified searching PubMed, Web of Science, Scopus, medRxiv using Medical Subject Headings (MeSH) terms COVID-19 OR coronavirus OR SARS-CoV-2 OR 2019-nCoV from 1 December 2019 to 15 August 2020 following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. PARTICIPANTS: Studies having biomarkers, including lymphocyte, platelets, D-dimer, lactate dehydrogenase (LDH), C reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, procalcitonin (PCT) and creatine kinase (CK), and describing outcomes were selected with the consensus of three independent reviewers. MAIN OUTCOME MEASURES: Composite poor outcomes include intensive care unit admission, oxygen saturation <90%, invasive mechanical ventilation utilisation, severe disease, in-hospital admission and mortality. The OR and 95% CI were obtained and forest plots were created using random-effects models. Publication bias and heterogeneity were assessed by sensitivity analysis. RESULTS: 32 studies with 10 491 confirmed COVID-19 patients were included. We found that lymphopenia (pooled-OR: 3.33 (95% CI: 2.51-4.41); p<0.00001), thrombocytopenia (2.36 (1.64-3.40); p<0.00001), elevated D-dimer (3.39 (2.66-4.33); p<0.00001), elevated CRP (4.37 (3.37-5.68); p<0.00001), elevated PCT (6.33 (4.24-9.45); p<0.00001), elevated CK (2.42 (1.35-4.32); p=0.003), elevated AST (2.75 (2.30-3.29); p<0.00001), elevated ALT (1.71 (1.32-2.20); p<0.00001), elevated creatinine (2.84 (1.80-4.46); p<0.00001) and LDH (5.48 (3.89-7.71); p<0.00001) were independently associated with higher risk of poor outcomes. CONCLUSION: Our study found a significant association between lymphopenia, thrombocytopenia and elevated levels of CRP, PCT, LDH, D-dimer and COVID-19 severity. The results have the potential to be used as an early biomarker to improve the management of COVID-19 patients, by identification of high-risk patients and appropriate allocation of healthcare resources in the pandemic.

Ibrutinib dose modifications in the management of CLL.

BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) in 2014. Ibrutinib is often used to treat patients who are younger than the patients originally included in theclinical trials have additional unfavorable prognostic factors and suffer from additional comorbidities excluded from the original phase III trials. Our objective was to examine current clinical practices and their impact in this expanded population of CLL patients who often require adjustments in the standard prescribed dose and schedule of therapy. MATERIALS AND METHODS: An extensive review of the medical literature was conducted to establish the consensus on ibrutinib dose modifications in patients with CLL. Twenty-nine studies were reviewed including fourteen clinical trials and fifteen "real-world practice" studies. RESULTS: The average discontinuation rate was similar between clinical trials and "real-world practice" studies though the reasons for discontinuation differed. CLL progression was a more common reason for discontinuation in clinical trial studies while toxicity was a more common reason for discontinuation in "real-world practice" studies. Some studies have suggested worse outcomes in patients requiring dose reductions in ibrutinib while others have shown no change in treatment efficacy in patients requiring dose reductions due to concomitant CYP medications or increased immunosuppression post-transplant. CONCLUSION: The impact of ibrutinib dose modifications on clinical outcome remains unclear. Patients on concomitant CYP3A inhibitors should be prescribed a lower dose than the standard 420 mg daily, in order to maintain comparable pharmacologic properties. Further research is required to establish definitive clinical practice guidelines.

Evaluating the impact of a health hackathon on collaborative team science: a Social Network Analysis (SNA).

The Mount Sinai Health Hackathon is designed to provide a novel forum to foster experiential team science training. Utilizing a Social Network Analysis survey, we studied the impact of the Mount Sinai Health Hackathon on the nature of collaborative relationships of hackathon participants. After the event, the number of links between participants from different disciplines increased and network density overall increased, suggesting a more interconnected network with greater interdisciplinary communication. This social network approach may be a useful addition to the evaluation strategies for team science education initiatives.

Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3ß (GSK3ß), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK3ß is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD-targeted therapy of AML patients. Mol Cancer Ther; 17(9); 1871-80. ©2018 AACR.

Serpentine Supravenous Hyperpigmentation in an HIV Patient Receiving R-CHOP for DLBCL.

Serpentine supravenous hyperpigmentation (SSH) is a rare vasculo-cutaneous entity that has been associated with peripheral infusion of chemotherapy agents, in particular 5-FU1-3, but also seen with docetaxel4,5, fotemustine6, and vinorelbine7. It consists of a marked hyperpigmentation along the superficial network of veins proximal to the chemotherapy infusion site and was originally described in a 1976 case report in association with 5-FU1. Here, for the first time, we report SSH in association with R-CHOP chemotherapy.

Creating effective career development programs.

This paper is the fourth in a 5-part series that focuses on educating and training the clinical and translational science workforce. The goal of this paper is to delineate components of effective career development programs that go beyond didactic training. All academic health centers with a Clinical and Translational Science Award have a KL2 career development award for junior faculty, and many also have a TL1 training program for predoctoral and postdoctoral fellows. The training across these programs varies, however junior investigators across the United States experience similar challenges. Junior investigators can get overwhelmed with the demands of building their own research program, particularly in academia. 1Often, they are sidetracked by competing demands that can derail their progress. In these situations, junior investigators experience frustration and may search for alternative career paths. By providing them with additional professional skills in the 5 domains of: (1) self-awareness; (2) selecting the right topic and securing funding; (3) getting adequate support; (4) working with others; and (5) managing yourself, your career, and your demands. We will give junior investigators additional tools to manage these demands and facilitate their own career success.

Accelerators: Sparking Innovation and Transdisciplinary Team Science in Disparities Research.

Development and implementation of effective, sustainable, and scalable interventions that advance equity could be propelled by innovative and inclusive partnerships. Readied catalytic frameworks that foster communication, collaboration, a shared vision, and transformative translational research across scientific and non-scientific divides are needed to foster rapid generation of novel solutions to address and ultimately eliminate disparities. To achieve this, we transformed and expanded a community-academic board into a translational science board with members from public, academic and private sectors. Rooted in team science, diverse board experts formed topic-specific "accelerators", tasked with collaborating to rapidly generate new ideas, questions, approaches, and projects comprising patients, advocates, clinicians, researchers, funders, public health and industry leaders. We began with four accelerators-digital health, big data, genomics and environmental health-and were rapidly able to respond to funding opportunities, transform new ideas into clinical and community programs, generate new, accessible, actionable data, and more efficiently and effectively conduct research. This innovative model has the power to maximize research quality and efficiency, improve patient care and engagement, optimize data democratization and dissemination among target populations, contribute to policy, and lead to systems changes needed to address the root causes of disparities.

Transition to Independence: Characteristics and Outcomes of Mentored Career Development (KL2) Scholars at Clinical and Translational Science Award Institutions.

PURPOSE: To describe the transition from mentored to independent research funding for clinical and translational scholars supported by institutional KL2 Mentored Career Development programs. METHOD: In 2013, faculty leaders at Clinical and Translational Science Award institutions completed an online survey, reporting characteristics of scholars in their KL2 programs from 2006 to 2013. The primary outcome variable was a report that the scholar had received independent funding as a principal investigator. Data analysis included descriptive summaries and mixed-effects regression models. RESULTS: Respondents from 48 institutions (of 62 eligible; 77%) provided information about 914 KL2 scholars. Of those, 620 (68%) were medical doctors, 114 (12%) had other clinical training, and 177 (19%) were nonclinician PhDs. Fifty-three percent (487) were female; 12% (108/865) were members of racial or ethnic groups underrepresented in medicine (URM). After completing KL2 training, 96% (558/582) remained engaged in research. Among scholars who completed KL2 training two or more years earlier, 39% (149/374) received independent funding. Independent funding was from non-National Institutes of Health (NIH) sources (120 scholars) more often than from NIH (101 scholars). The odds of a nonclinician attaining independent funding were twice those of a clinician (odds ratio 2.05; 95% confidence interval 1.11-3.78). Female and URM scholars were as likely as male and non-URM scholars to attain independent funding. CONCLUSIONS: KL2 programs supported the transition to independent funding for clinical and translational scientists. Female and URM scholars were well represented. Future studies should consider non-NIH funding sources when assessing the transition to research independence.

Sorafenib Inhibition of Mcl-1 Accelerates ATRA-Induced Apoptosis in Differentiation-Responsive AML Cells.

PURPOSE: All trans-retinoic acid (ATRA) is successful in treating acute promyelocytic leukemia (APL) by inducing terminal differentiation-mediated cell death, but it has limited activity in non-APL acute myeloid leukemia (AML). We aim to improve ATRA therapy of AML by enhancing apoptosis through repression of the antiapoptotic proteins Bcl-2 and Mcl-1. EXPERIMENTAL DESIGN: APL and AML cell lines, as well as primary AML samples, were used to explore the mechanisms regulating differentiation and apoptosis during ATRA treatment. Stable transfection and gene silencing with siRNA were used to identify the key factors that inhibit apoptosis during induction of differentiation and drugs that accelerate apoptosis. RESULTS: In differentiation-responsive AML cells, ATRA treatment induces long-lasting repression of Bcl-2 while first upmodulating and then reducing the Mcl-1 level. The Mcl-1 level appears to serve as a gatekeeper between differentiation and apoptosis. During differentiation induction, activation of MEK/ERK and PI3K/Akt pathways by ATRA leads to activation of p90RSK and inactivation of glycogen synthase kinase 3ß (GSK3ß), which increase Mcl-1 levels by increasing its translation and stability. Sorafenib blocks ATRA-induced Mcl-1 increase by reversing p90RSK activation and GSK3ß inactivation, maintains the repressed Bcl-2 level, and enhances ATRA induced apoptosis in non-APL AML cell lines and in primary AML cells. CONCLUSIONS: Inhibition of Mcl-1 is required for apoptosis induction in ATRA differentiation-responsive AML cells. ATRA and sorafenib can be developed as a novel drug combination therapy for AML patients because this drug combination augments apoptosis by inhibiting Bcl-2 and Mcl-1.

Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.