Key Informants' Perceptions of Health Equity and Racial Justice Impacts of the 2019 Massachusetts An Act Modernizing Tobacco Control.

INTRODUCTION: The Massachusetts legislature passed An Act Modernizing Tobacco Control in November 2019 to restrict retail sales of flavored commercially manufactured tobacco products including menthol products, increase penalties for violating the law's provisions, and provide health insurance coverage for tobacco treatment. AIMS AND METHODS: This study explores key informants' perceptions of intended and unintended impacts of implementation of the 2019 Massachusetts statewide law through a health equity and racial justice lens. We conducted in-depth interviews with 25 key informants from three key informant groups (public health officials and advocates, clinicians, and school staff) between March 2021 and April 2022. Using deductive codes on unintended impacts of the implementation of the law's policies, we conducted a focused analysis to identify impacts that were perceived and observed by informants from different key informant groups. RESULTS: Perceived or observed impacts of the law were identified across multiple levels by key informants and included concerns related to three broad themes: 1) intended impacts on health equity and racial justice, 2) ongoing availability of restricted products undermining the intended impact of the law, and 3) inequitable targeting by the policies and enforcement among communities of color. CONCLUSIONS: Future evaluation is needed to assess the intended and unintended impacts of implementation of the Massachusetts law to maximize the potential of the policies to reduce tobacco-related health disparities. We discuss implications and recommendations for achieving a national policy and equitable enforcement of flavored tobacco sales restrictions. IMPLICATIONS: This qualitative study among 25 key informants including public health and tobacco control advocates, clinicians, and school staff obtained perspectives of intended and unintended health equity and racial justice impacts of the 2019 Massachusetts An Act Modernizing Tobacco Control. Findings and recommendations from this study can inform monitoring efforts to assess the law's impacts in Massachusetts and the adoption of similar flavored tobacco sales restrictions and other tobacco control policies in other states to maximize the health equity benefits and minimize unintended impacts.

Fascin structural plasticity mediates flexible actin bundle construction.

Fascin crosslinks actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during metastasis, and fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-electron microscopy, cryo-electron tomography coupled with custom denoising, and computational modeling to probe fascin's F-actin crosslinking mechanisms across spatial scales. Our fascin crossbridge structure reveals an asymmetric F-actin binding conformation that is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis, and simulations show how structural plasticity enables fascin to bridge varied inter-filament orientations, accommodating mismatches between F-actin's helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncovers geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable crosslinks that limit bundle size. Collectively, this work shows how fascin harnesses fine-tuned nanoscale structural dynamics to build and regulate micron-scale F-actin bundles.

Barriers and facilitators to address vaping in Massachusetts schools: a mixed-methods study of school-based stakeholders.

We assessed vaping behaviors, environments, COVID-19 influences, and barriers and facilitators of existing approaches that address adolescent vaping in Massachusetts middle and high schools. Findings from this study will provide considerations for individual schools or districts as they advance adolescent vaping prevention and treatment efforts. We analyzed 310 open-ended comments from Massachusetts school administrators who completed a survey between November 2020 and January 2021. Further, we analyzed nine semi-structured interviews with administrators (e.g., principals, vice principals, school nurses) from Massachusetts school systems (n = 6) and school-based anti-tobacco advocates (n = 3); interviews took place between May and December 2021. Informed by Green's PRECEDE model, we conducted a framework analysis using deductive codes based on the model constructs (enabling, reinforcing, and predisposing factors) and inductive codes of key themes emerging from the interviews. Challenges to addressing adolescent vaping included staff capacity, funding, and lack of mental health and counseling supports. The COVID-19 pandemic was a major barrier to conducting usual in-person vaping programs, but also reduced student vaping at school due to new social distancing practices and bathroom use policies. Facilitators of vaping interventions included peer-led initiatives and parental involvement. Participants discussed the importance of educating adolescents on the harms of vaping and the move toward alternatives-to-suspension programs rather than disciplinary action. School-based anti-vaping program implementers-such as school districts, state departments of education, or local health departments-will need to leverage facilitators such as peer-led initiatives, alternatives-to-suspension approaches, and parental involvement, to increase the potential impact of these programs.

The purpose of this study was to understand challenges that school administrators faced in their approaches to address adolescent vaping in Massachusetts middle and high schools. We analyzed open-ended comments from Massachusetts school administrators who completed a survey between November 2020 and January 2021. Further, we analyzed nine interviews with administrators (e.g., principals, vice principals, school nurses) from Massachusetts school systems (n = 6) and school-based anti-tobacco advocates (n = 3); interviews took place between May and December 2021. We found that challenges to addressing adolescent vaping included school personnel capacity, funding, and lack of mental health and counseling supports. The COVID-19 pandemic was a major barrier to conducting usual in-person vaping programs, but also reduced student vaping at school due to new social distancing practices and bathroom use policies. Successful approaches included peer-led initiatives and parental involvement, and participants discussed the importance of educating adolescents on the harms of vaping. Based on our findings, school-based anti-vaping program practitioners­such as school districts, state departments of education, or local health departments­should leverage peer-led initiatives, alternatives-to-suspension approaches, and parental involvement, to increase the potential impact of adolescent vaping prevention and treatment efforts.

The Use of Natural Language Processing to Assess Social Support in Patients With Advanced Cancer.

BACKGROUND: Data examining associations among social support, survival, and healthcare utilization are lacking in patients with advanced cancer. METHODS: We conducted a cross-sectional secondary analysis using data from a prospective longitudinal cohort study of 966 hospitalized patients with advanced cancer at Massachusetts General Hospital from 2014 through 2017. We used NLP to identify extent of patients' social support (limited versus adequate as defined by NLP-aided review of the Electronic Health Record (EHR)). Two independent coders achieved a Kappa of 0.90 (95% CI: 0.84-1.00) using NLP. Using multivariable regression models, we examined associations of social support with: 1) OS; 2) death or readmission within 90 days of hospital discharge; 3) time to readmission within 90 days; and 4) hospital length of stay (LOS). RESULTS: Patients' median age was 65 (range: 21-92) years, and a plurality had gastrointestinal (GI) cancer (34.3%) followed by lung cancer (19.5%). 6.2% (60/966) of patients had limited social support. In multivariable analyses, limited social support was not significantly associated with OS (HR = 1.13, P = 0.390), death or readmission (OR = 1.18, P = 0.578), time to readmission (HR = 0.92, P = 0.698), or LOS (ß = -0.22, P = 0.726). We identified a potential interaction suggesting cancer type (GI cancer versus other) may be an effect modifier of the relationship between social support and OS (interaction term P = 0.053). In separate unadjusted analyses, limited social support was associated with lower OS (HR = 2.10, P = 0.008) in patients with GI cancer but not other cancer types (HR = 1.00, P = 0.991). CONCLUSION: We used NLP to assess the extent of social support in patients with advanced cancer. We did not identify significant associations of social support with OS or healthcare utilization but found cancer type may be an effect modifier of the relationship between social support and OS. These findings underscore the potential utility of NLP for evaluating social support in patients with advanced cancer.

Relationship Between Longitudinal Coping Strategies and Outcomes in Patients With Acute Myeloid Leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) face an abrupt life-threatening illness and experience immense physical and psychological symptoms. However, no data describe how patients with AML cope longitudinally with their illness or the relationship between longitudinal coping and outcomes. METHODS: We conducted a secondary analysis of longitudinal data from 160 patients with high-risk AML enrolled in a supportive care intervention trial to describe coping strategies longitudinally across the illness course. We used the Brief COPE questionnaire, the Hospital Anxiety and Depression Scale, the Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Functional Assessment of Cancer Therapy-Leukemia to measure coping strategies, psychological distress, and quality of life (QoL) at baseline and at weeks 2, 4, 12, and 24 after diagnosis. Electronic health records were used to assess healthcare utilization and end-of-life (EoL) outcomes, and multivariate analyses were used to assess the relationship between coping and outcomes. RESULTS: Longitudinal utilization of approach-oriented coping strategies was significantly associated with less distress (anxiety: ß, -0.18; P<.001; depression symptoms: ß, -0.42; P<.001; PTSD symptoms: ß, -0.60; P<.001) and better QoL (ß, 2.00; P<.001). Longitudinal utilization of avoidant coping strategies was significantly associated with greater distress (anxiety: ß, 0.64; depression symptoms: ß, 0.54; PTSD symptoms: ß, 2.13; P<.001 for all) and worse QoL (ß, -4.27; P<.001). Although the use of approach-oriented and avoidant coping strategies was not significantly associated with hospitalization, chemotherapy administration, or hospice use in the last 30 days of life, approach-oriented coping was associated with lower odds of ICU admissions (odds ratio, 0.92; P=.049). CONCLUSIONS: Longitudinal use of approach-oriented coping strategies was associated with less psychological distress, better QoL, and a lower likelihood of ICU admission, suggesting a possible target for supportive oncology interventions. Coping strategies did not impact EoL outcomes, and further research is needed to elucidate which patient factors impact EoL decision-making.

Bending forces and nucleotide state jointly regulate F-actin structure.

ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation1-3. In turn, force4,5 and actin filament (F-actin) nucleotide state6 regulate actin dynamics by tuning F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-Pi-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-Pi-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.

Structural mechanism for bidirectional actin cross-linking by T-plastin.

To orchestrate cell mechanics, trafficking, and motility, cytoskeletal filaments must assemble into higher-order networks whose local subcellular architecture and composition specify their functions. Cross-linking proteins bridge filaments at the nanoscale to control a network's µm-scale geometry, thereby conferring its mechanical properties and functional dynamics. While these interfilament linkages are key determinants of cytoskeletal function, their structural mechanisms remain poorly understood. Plastins/fimbrins are an evolutionarily ancient family of tandem calponin-homology domain (CHD) proteins required to construct multiple classes of actin networks, which feature diverse geometries specialized to power cytokinesis, microvilli and stereocilia biogenesis, and persistent cell migration. Here, we focus on the structural basis of actin network assembly by human T-plastin, a ubiquitously expressed isoform necessary for the maintenance of stable cellular protrusions generated by actin polymerization forces. By implementing a machine-learning-enabled cryo-electron microscopy pipeline for visualizing cross-linkers bridging multiple filaments, we uncover a sequential bundling mechanism enabling T-plastin to bridge pairs of actin filaments in both parallel and antiparallel orientations. T-plastin populates distinct structural landscapes in these two bridging orientations that are selectively compatible with actin networks featuring divergent architectures and functions. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable cross-linking that are likely to be disrupted by T-plastin mutations that cause hereditary bone diseases.

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia.

The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and mutations in myosin-15 cause hereditary deafness. In addition to transporting actin regulatory machinery to stereocilia tips, myosin-15 directly nucleates actin filament ("F-actin") assembly, which is disrupted by a progressive hearing loss mutation (p.D1647G, "jordan"). Here, we present cryo-electron microscopy structures of myosin-15 bound to F-actin, providing a framework for interpreting the impacts of deafness mutations on motor activity and actin nucleation. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin's D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. Adenosine diphosphate-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin's structural plasticity in a myosin nucleotide state-dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

Code status transitions in patients with high-risk acute myeloid leukemia.

Patients with high-risk acute myeloid leukemia (AML) often experience intensive medical care at the end of life (EOL), including high rates of hospitalizations and intensive care unit (ICU) admissions. Despite this, studies examining code status transitions are lacking. We conducted a mixed-methods study of 200 patients with high-risk AML enrolled in supportive care studies at Massachusetts General Hospital between 2014 and 2021. We defined high-risk AML as relapsed/refractory or diagnosis at age ≥60. We used a consensus-driven medical record review to characterize code status transitions. At diagnosis, 86.0% (172/200) of patients were "full code" (38.5% presumed, 47.5% confirmed) and 8.5% had restrictions on life-sustaining therapies. Overall, 57.0% of patients experienced a transition during the study period. The median time from the last transition to death was 2 days (range, 0-350). Most final transitions (71.1%) were to comfort measures near EOL; only 60.5% of patients participated in these last transitions. We identified 3 conversation types leading to transitions: informative conversations focusing on futility after clinical deterioration (51.0%), anticipatory conversations at the time of acute deterioration (32.2%), and preemptive conversations (15.6%) before deterioration. Younger age (B = 0.04; P = .002) and informative conversations (B = -2.79; P < .001) were associated with shorter time from last transition to death. Over two-thirds of patients were "presumed full code" at diagnosis of high-risk AML, and most experienced code status transitions focused on the futility of continuing life-sustaining therapies near EOL. These results suggest that goals-of-care discussions occur late in the illness course for patients with AML and warrant interventions to increase earlier discussions regarding EOL preferences.

The First State Tobacco Flavor Ban: High School Tobacco Control Needs in a Changing Landscape.

BACKGROUND: Despite recent tobacco control efforts, adolescent vaping remains an epidemic in the United States. The purpose of our study was to understand high school student vaping behaviors using the perceptions of Massachusetts school personnel during the critical window from when the Massachusetts statewide flavor ban legislation was passed in November 2019 through the first year of the COVID-19 pandemic. METHODS: High school personnel throughout Massachusetts were invited to complete a cross-sectional survey. Analysis of survey responses was conducted in R. RESULTS: A total of 162 respondents completed the survey representing 137 schools that draw enrollments from 216 (61%) of the 352 cities and towns in Massachusetts. The most popular products that respondents believed their students were using were JUULs (95.7%), other e-cigarettes (85.3%), and disposable vapes (79.6%). Following the flavor ban, the majority (90.7%) did not report an increase in combusted tobacco product use. All participants (100%) reported wanting more access to prevention and treatment resources. CONCLUSIONS: Our findings suggest that a comprehensive flavor ban may be an effective tobacco control policy that does not appear to promote student switching from vaping products to combusted tobacco products. These data also indicate that schools report needing additional resources to address the vaping epidemic.

Factors Associated with Health Care Utilization at the End of Life for Patients with Acute Myeloid Leukemia.

Background: Patients (≥60 years) with acute myeloid leukemia (AML) often receive intense health care utilization at the end of life (EOL). However, factors associated with their health care use at the EOL are unknown. Methods: We conducted a secondary analysis of 168 deceased patients with AML within the United States. We assessed quality of life (QOL) (Functional-Assessment-Cancer-Therapy-Leukemia), and psychological distress (Hospital-Anxiety-and-Depression Scale [HADS]; Patient-Health-Questionnaire-9 [PHQ-9]) at diagnosis. We used multivariable logistic regression models to examine the association between patient-reported factors and the following outcomes: (1) hospitalizations in the last 7 days of life, (2) receipt of chemotherapy in the last 30 days of life, and (3) hospice utilization. Results: About 66.7% (110/165) were hospitalized in the last 7 days of life, 51.8% (71/137) received chemotherapy in the last 30 days of life, and 40.7% (70/168) utilized hospice. In multivariable models, higher education (odds ratio [OR] = 1.54, p = 0.006) and elevated baseline depression symptoms (PHQ-9: OR = 1.09, p = 0.028) were associated with higher odds of hospitalization in the last seven days of life, while higher baseline QOL (OR = 0.98, p = 0.009) was associated with lower odds of hospitalization at the EOL. Higher baseline depression symptoms were associated with receipt of chemotherapy at the EOL (HADS-Depression: OR = 1.10, p = 0.042). Higher education was associated with lower hospice utilization (OR = 0.356, p = 0.024). Conclusions: Patients with AML who are more educated, with higher baseline depression symptoms and lower QOL, were more likely to experience high health care utilization at the EOL. These populations may benefit from interventions to optimize the quality of their EOL care.

Coping strategies in patients with acute myeloid leukemia.

Patients diagnosed with acute myeloid leukemia (AML) face sudden-onset life-threatening disease that requires intensive treatments. Although their early disease trajectory is characterized by significant, toxic side effects, limited data are available describing coping strategies among patients with AML and how these inform patient-reported outcomes. We used cross-sectional secondary data analyses to describe coping in 160 patients with newly diagnosed high-risk AML. The Brief COPE, Hospital Anxiety and Depression Scale, Post-Traumatic Stress Disorder Checklist-Civilian Version, and Functional Assessment of Cancer Therapy-Leukemia were used at time of AML diagnosis to measure coping strategies, psychological distress, and quality of life (QOL), respectively. The median split method for distribution of coping domains and multivariate regression models were used to assess the relationship between coping and patient-reported outcomes. Participants (median age, 64.4 years) were mostly non-Hispanic White (86.3%), male (60.0%), and married (73.8%). Most (51.9%) had high utilization of approach-oriented coping strategies, whereas 38.8% had high utilization of avoidant coping strategies. At time of diagnosis, use of approach-oriented coping was associated with less psychological distress (anxiety, ß = -0.262, P = .002; depression symptoms, ß = -0.311, P < .001; and posttraumatic distress disorder symptoms, ß = -0.596, P = .006) and better QOL (ß = 1.491, P = .003). Use of avoidant coping was associated with more psychological distress (anxiety, ß = 0.884, P < .001; depression symptoms, ß = 0.697, P < .001; and posttraumatic distress disorder symptoms, ß = 3.048, P < .001) and worse QOL (ß = -5.696, P < .001). Patients with high-risk AML use various approach-oriented and avoidant coping strategies at time of diagnosis. Use of approach-oriented coping strategies was associated with less psychological distress and better QOL, suggesting a possible target for supportive oncology interventions.

End-of-Life Care for Older Adults with Aggressive Non-Hodgkin Lymphoma.

Background: Aggressive non-Hodgkin lymphoma (NHL) commonly affects older adults and is often treated with intensive therapies. Receipt of intensive therapies and absence of a clear transition between the curative and palliative phases of treatment yield prognostic uncertainty and risk for poor end-of-life (EOL) outcomes. However, data regarding the EOL outcomes of this population are lacking. Methods: We conducted a retrospective analysis of adults ≥65 years with aggressive NHL treated with systemic therapy at Massachusetts General Hospital from April 2000 to July 2020 who subsequently died. We abstracted patient and clinical characteristics and EOL outcomes from the medical record. Using multivariable logistic regression, we examined factors associated with hospitalization within 30 days of death and hospice utilization. Results: Among 91 patients (median age = 75 years; 37.4% female), 70.3% (64/91) were hospitalized, 34.1% (31/91) received systemic therapy, and 23.3% (21/90) had an intensive care unit admission within 30 days of death. The rates of palliative care consultation and hospice utilization were 47.7% (42/88) and 39.8% (35/88), respectively. More than half of patients (51.6%, 47/91) died in a hospital or health care facility. In multivariable analysis, elevated lactic acid dehydrogenase was associated with risk of hospitalization within 30 days of death (odds ratio [OR] 3.61, p = 0.014). Palliative care consultation (OR 4.45, p = 0.005) was associated with a greater likelihood of hospice utilization, whereas hypoalbuminemia (OR 0.29, p = 0.026) was associated with a lower likelihood of hospice utilization. Conclusions: Older adults with aggressive NHL often experience high health care utilization and infrequently utilize hospice care at the EOL. Our findings underscore the need for interventions to optimize the quality of EOL care for this population.

Association of Social Support With Overall Survival and Healthcare Utilization in Patients With Aggressive Hematologic Malignancies.

BACKGROUND: Social support plays a crucial role for patients with aggressive hematologic malignancies as they navigate their illness course. The aim of this study was to examine associations of social support with overall survival (OS) and healthcare utilization in this population. METHODS: A cross-sectional secondary analysis was conducted using data from a prospective longitudinal cohort study of 251 hospitalized patients with aggressive hematologic malignancies at Massachusetts General Hospital from 2014 through 2017. Natural Language Processing (NLP) was used to identify the extent of patients' social support (limited vs adequate as defined by NLP-aided chart review of the electronic health record). Multivariable regression models were used to examine associations of social support with (1) OS, (2) death or readmission within 90 days of discharge from index hospitalization, (3) time to readmission within 90 days, and (4) index hospitalization length of stay. RESULTS: Patients had a median age of 64 years (range, 19-93 years), and most were White (89.6%), male (68.9%), and married (65.3%). A plurality of patients had leukemia (42.2%) followed by lymphoma (37.9%) and myelodysplastic syndrome/myeloproliferative neoplasm (19.9%). Using NLP, we identified that 8.8% (n=22) of patients had limited social support. In multivariable analyses, limited social support was associated with worse OS (hazard ratio, 2.00; P=.042) and a higher likelihood of death or readmission within 90 days of discharge (odds ratio, 3.11; P=.043), but not with time to readmission within 90 days or with index hospitalization length of stay. CONCLUSIONS: In this cohort of hospitalized patients with aggressive hematologic malignancies, we found associations of limited social support with lower OS and a higher likelihood of death or readmission within 90 days of hospital discharge. These findings underscore the utility of NLP for evaluating the extent of social support and the need for larger studies evaluating social support in patients with aggressive hematologic malignancies.

Distress in a Pandemic: Association of the Coronavirus Disease-2019 Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation.

The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients' distress levels. Patients undergoing hematopoietic stem cell transplantation (HSCT) may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and quality of life (QoL) are not well understood in this population. In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress symptoms (depression, anxiety, and posttraumatic stress disorder [PTSD]), fatigue, and QoL between enrollees before (ie, March 2019-January 2020) and during (ie, March 2020-January 2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semistructured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT. One hundred twenty-four participants enrolled before COVID-19, and 81 participants enrolled during the pandemic. The 2 cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QoL impairment. COVID-19-era participants reported themes of negative (eg, increased isolation) and positive (eg, engagement with meaningful activities) implications of the pandemic on HSCT recovery. We found no differences in pre-HSCT distress, fatigue, or QoL in patients undergoing HSCT before or during the COVID-19 pandemic; however, patients in early recovery post-HSCT report both negative and positive implications of the COVID-19 pandemic in their lives.

Clinical Outcomes, Treatment Toxicity, and Health Care Utilization in Older Adults with Aggressive Non-Hodgkin Lymphoma.

BACKGROUND: Although balancing treatment efficacy with risks of complications is critical for older adults with aggressive non-Hodgkin lymphoma (NHL), few studies have described these patients' clinical outcomes, rates of toxicities, and health care utilization. METHODS: We conducted a retrospective analysis of adults ≥65 years diagnosed with aggressive NHL and receiving systemic therapy at Massachusetts General Hospital from April 2000 to July 2020. We abstracted patient characteristics, clinical outcomes, treatment toxicity, unplanned hospitalizations, and intensive care unit (ICU) admissions within 6 months of treatment initiation from the medical record. Using multivariable logistic regression, we examined factors associated with rates of grade 3+ nonhematologic toxicity and unplanned hospitalization. RESULTS: Among 295 patients (median age, 73 years; 39.0% female), 5-year overall survival (OS) was 74.2%. Five-year OS by age group (65-69, 70-74, 75-79, and 80+ years) was 82.2%, 72.0%, 73.6%, and 66.4%, respectively. Overall, 42.4% experienced grade 3+ toxicity, with 8.1% experiencing grades 4-5. The rates of unplanned hospitalization and ICU admission were 41.0% and 6.1%, respectively. In multivariable analysis, hypoalbuminemia (odds ratio [OR], 4.29; p < .001) and high comorbidity score (OR, 4.22; p < .001) were associated with likelihood of grade 3+ toxicity. Hypoalbuminemia (OR, 2.83; p = .003), high comorbidity score (OR, 3.93; p = .001), and receipt of EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; OR, 5.45; p = .012) were associated with likelihood of unplanned hospitalization. CONCLUSIONS: The majority of older adults receiving upfront therapy for aggressive NHL survive beyond 5 years, yet nearly half experience substantial treatment toxicities and unplanned hospitalizations. Our findings underscore the need for supportive care interventions to enhance the care experience of this population. IMPLICATIONS FOR PRACTICE: The results of this study highlight the potential benefits of intensive chemoimmunotherapy for the majority of older adults with aggressive non-Hodgkin lymphoma, even at advanced ages. Nearly half of older adults experienced substantial treatment toxicities and unplanned hospitalizations, emphasizing the unmet need for supportive care interventions in this population. The present study also identified hypoalbuminemia and patient comorbidity score as factors associated with grade 3+ nonhematologic toxicity and unplanned hospitalization. These findings may guide the development and implementation of targeted supportive care interventions in high-risk older adults with aggressive non-Hodgkin lymphoma.

Association Between Baseline Patient-Reported Outcomes and Complications of Hematopoietic Stem Cell Transplantation.

Hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies, but it often results in significant toxicities and impaired quality of life (QOL). Although the value of patient-reported outcomes (PROs) is increasingly recognized in HCT, data are limited regarding the relationship between PROs and HCT complications. We conducted a secondary data analysis of 250 patients who were hospitalized for autologous or allogeneic HCT at Massachusetts General Hospital from 2011 through 2016. We assessed QOL (Functional Assessment of Cancer Therapy-General), mood (Hospital Anxiety and Depression Scale), and fatigue (FACT-Fatigue) at baseline. We abstracted from the Electronic Health Record (1) hospitalization during the first 100 days after HCT, (2) days alive and out of the hospital in the first 100 days after HCT, and (3) cumulative incidence of acute graft-versus-host disease (GVHD) among allogeneic HCT recipients. We assessed the association of baseline PROs with HCT complications using multivariable models adjusting for patient and transplant characteristics. Overall, 44.4% (111/250) of patients underwent an autologous HCT, 25.2% (63/250) received a myeloablative allogeneic HCT, and 30.4% (76/250) underwent a reduced-intensity allogeneic HCT. In multivariable logistic regression, higher anxiety (odds ratio [OR] = 1.14, P = .004) was associated with higher likelihood of rehospitalization within 100 days after HCT. In multivariable Poisson regression, lower fatigue (ß = 0.003, P = .015) was associated with increased days alive and out of the hospital in the first 100 days post-HCT. In multivariable logistic regression, lower baseline QOL (OR = 0.97, P = .034), higher fatigue (OR = 0.95, P = .004), and higher depression (OR = 1.15, P = .020) were associated with increased likelihood of acute GVHD. Baseline PROs are associated with health care utilization after HCT and risk of acute GVHD in allogeneic HCT recipients. These findings underscore the potential utility of pretransplantation PROs as important prognostic factors for HCT.

Palliative care for patients undergoing stem cell transplant: intervention components and supportive care measures.

An inpatient palliative care intervention during HCT led to improvement in patient QOL and mood. We sought to describe components of the intervention, investigate differences in supportive care practices by treatment arm, and explore whether these differences mediated the impact of the intervention on patient QOL and mood. We conducted a secondary analysis of a randomized trial investigating inpatient palliative care integrated with transplant care versus standard transplant care for HCT recipients. Palliative care clinicians completed weekly surveys to describe topics addressed during visits. We extracted use of supportive care medications from the medical record. Participants completed QOL and mood assessments at baseline and two weeks post-HCT. Causal mediation assessed whether differences in supportive care practices mediated the impact of the intervention on patient-reported outcomes. A total of 160 HCT recipients participated. Palliative care visits most frequently focused on managing symptoms and coping with HCT. Patients randomized to the intervention were more likely to use Patient-Controlled Analgesia (PCA) (32.1% vs. 15.2%, p = 0.02) and atypical antipsychotics (35.8% vs. 17.7%, p = 0.01). Neither PCA nor atypical antipsychotics mediated the effect of the intervention on patient-reported outcomes. Future work to explore mechanisms by which the palliative care intervention improves QOL and mood is needed.

Clinical Outcomes of Patients Hospitalized with Coronavirus Disease 2019 (COVID-19) in Boston.

BACKGROUND: Outcomes of hospitalized patients with COVID-19 have been described in health systems overwhelmed with a surge of cases. However, studies examining outcomes of patients admitted to hospitals not in crisis are lacking. OBJECTIVE: To describe clinical characteristic and outcomes of all patients with COVID-19 who are admitted to hospitals not in crisis, and factors associated with mortality in this population. DESIGN: A retrospective analysis PARTICIPANTS: In total, 470 consecutive patients with COVID-19 requiring hospitalization in one health system in Boston from January 1, 2020 to April 15, 2020. MAIN MEASURES: We collected clinical outcomes during hospitalization including intensive care unit (ICU) admission, receipt of mechanical ventilation, and vasopressors. We utilized multivariable logistic regression models to examine factors associated with mortality. KEY RESULTS: A total of 470 patients (median age 66 [range 23-98], 54.0% male) were included. The most common comorbidities were diabetes (38.5%, 181/470) and obesity (41.3%, 194/470). On admission, 41.9% (197/470) of patients were febrile and 60.6% (285/470) required supplemental oxygen. During hospitalization, 37.9% (178/470) were admitted to the ICU, 33.6% (158/470) received mechanical ventilation, 29.4% (138/470) received vasopressors, 16.4% (77/470) reported limitations on their desire for life-sustaining therapies such as intubation and cardiopulmonary resuscitation, and 25.1% (118/470) died. Among those admitted to the ICU (N=178), the median number of days on the ventilator was 10 days (IQR 1-29), and 58.4% (104/178) were discharged alive. Older age (OR=1.04, P<0.001), male sex (OR=2.14, P=0.007), higher comorbidities (OR=1.20, P=0.001), higher lactate dehydrogenase on admission (2nd tertile: OR=4.07, P<0.001; 3rd tertile: OR=8.04, P<0.001), and the need for supplemental oxygen on admission (OR=2.17, P=0.014) were all associated with higher mortality. CONCLUSIONS: The majority of hospitalized patients with COVID-19 and those who received mechanical ventilation survived. These data highlight the need to examine public health and system factors that contribute to improved outcomes for this population.

Single-molecule and in silico dissection of the interaction between Polycomb repressive complex 2 and chromatin.

Polycomb repressive complex 2 (PRC2) installs and spreads repressive histone methylation marks on eukaryotic chromosomes. Because of the key roles that PRC2 plays in development and disease, how this epigenetic machinery interacts with DNA and nucleosomes is of major interest. Nonetheless, the mechanism by which PRC2 engages with native-like chromatin remains incompletely understood. In this work, we employ single-molecule force spectroscopy and molecular dynamics simulations to dissect the behavior of PRC2 on polynucleosome arrays. Our results reveal an unexpectedly diverse repertoire of PRC2 binding configurations on chromatin. Besides reproducing known binding modes in which PRC2 interacts with bare DNA, mononucleosomes, and adjacent nucleosome pairs, our data also provide direct evidence that PRC2 can bridge pairs of distal nucleosomes. In particular, the "1-3" bridging mode, in which PRC2 engages two nucleosomes separated by one spacer nucleosome, is a preferred low-energy configuration. Moreover, we show that the distribution and stability of different PRC2-chromatin interaction modes are modulated by accessory subunits, oncogenic histone mutations, and the methylation state of chromatin. Overall, these findings have implications for the mechanism by which PRC2 spreads histone modifications and compacts chromatin. The experimental and computational platforms developed here provide a framework for understanding the molecular basis of epigenetic maintenance mediated by Polycomb-group proteins.