Citations

Abstract Introduction People with heart failure (HF) have frequent hospitalizations, and emergency department (ED) visits. We examined the effects of insomnia and rest-activity rhythms (RARs) on time to hospitalizations and ED visits after controlling for other known risk factors among participants in a randomized controlled trial of cognitive behavioral therapy for insomnia compared to heart failure self-management education (attention control). Methods The analysis included 168 HF patients who had available medical records for dates of hospitalization, ED visit, transplant, and death from a randomized clinical trial for insomnia of people with HF and insomnia. The known risk factors included age, sex, New York Heart Association (NYHA) Class, ejection fraction, and comorbid conditions. We used the insomnia severity index (ISI) and evaluated the strength of RAR using the ratio of the amplitude to the MESOR estimated with cosinor analysis with activity counts from a wrist-actigraph worn for at least five consecutive days. Cox proportional hazard models were used to examine ­insomnia and the RAR metrics with the known risk factors on time to first hospitalization, ED visit, transplant, and death. Results Eighty-five (50.1%) had at least one hospitalization, and ninety-one (54.2%) participants had an ED visit. Approximately 42% of the participants were admitted to the hospital due to cardiac events. Older age, male sex, higher NYHA, and greater comorbidity were associated with earlier hospitalization or ED visits. After controlling for those risk factors, stronger RAR was associated with later time to hospitalization, and ED visit with hazard ratios (HRs) of 0.26 (95% CI=[0.07, 0.91]) and 0.25 (95% CI=[0.07, 0.89]); higher insomnia severity (ISI ≥22) was associated with shorter time to ED visits, with an HR of 2.28 (95% CI=[1.19, 4.38]). Conclusion In addition to known demographic and clinical risk factors, insomnia severity and RAR predict hospitalizations and ED visits in people with HF. Further research is necessary to assess the biological mechanism of the associations and examine whether the effects of the risk factors could be modified by improving insomnia severity and RAR in people with HF. Support (if any) This study was financially supported by grants R01NR016191 and P20NR014126 from NIH/NINR.

Abstract Introduction Cognitive behavioral therapy for insomnia (CBT-I) improves individual symptoms of fatigue and daytime sleepiness; however, little is known how CBT-I improves multiple co-occurring daytime symptoms. The purposes of this study are to (1) identify daytime symptom trajectories in adults with insomnia and stable chronic heart failure (HF) over one year, and (2) determine how symptom trajectories vary based on participation in CBT-I or HF self-management education (attention control condition). Methods We conducted a retrospective analysis of data from a randomized controlled trial that looked the sustained effects of CBT-I compared to HF self-management over one year (NCT02660385). We measured daytime symptoms (fatigue, depression, anxiety, dyspnea, pain, and daytime sleepiness) at baseline (pre-treatment) and 3, 6 and 12 months. Symptom cluster trajectory were identified using group-based trajectory modeling, and the association with CBT-I was examined using logistic regressions. Results We randomized 175 participants (M age=63.0 (12.9) years, 57% men). We found four daytime symptom cluster trajectories, (A) low improving symptoms (N = 67, 38.3%); (B) low psychological symptoms and high improving physical symptoms (N = 40, 22.8%); (C), high improving symptoms (N = 42, 24.0%); and (D) high not improving symptoms (N = 26, 14.9%). There was no statistically significant difference between CBT-I and HF self-management across 4 symptom trajectories (p = .2509). However, people who received CBT-I vs. HF self-management education had higher odds of belonging to trajectory A compared to B/C/D after controlling for baseline fatigue (OR = 3.27 95% Confidence Intervals [1.39, 7.68]). Conclusion Most participants experienced improved daytime symptom profiles over 12 months after both interventions. Participants in the CBT-I group experienced symptom improvement even when they started with low symptoms. Support (if any) National Institute of Nursing Research [R01NR016191 and P20NR014126].

ImportanceProgressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease.ObjectiveTo describe characteristics of patients with S-PML.Design, Setting, and ParticipantsFor this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023.ExposuresSarcoidosis without active therapeutic immune suppression.Main Outcomes and MeasuresClinical, laboratory, and radiographic features of patients with S-PML.ResultsTwenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/μL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not.Conclusions and RelevanceIn this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

In cancer cells, endogenous or therapy-induced DNA damage leads to the abnormal presence of DNA in the cytoplasm, which triggers the activation of cGAS (cyclic GMP–AMP synthase) and STING (stimulator of interferon genes). STAT2 suppresses the cGAMP-induced expression of IRF3-dependent genes by binding to STING, blocking its intracellular trafficking, which is essential for the full response to STING activation. STAT2 reshapes STING signaling by inhibiting the induction of IRF3-dependent, but not NF-κB–dependent genes. This noncanonical activity of STAT2 is regulated independently of its tyrosine phosphorylation but does depend on the phosphorylation of threonine 404, which promotes the formation of a STAT2:STING complex that keeps STING bound to the endoplasmic reticulum (ER) and increases resistance to DNA damage. We conclude that STAT2 is a key negative intracellular regulator of STING, a function that is quite distinct from its function as a transcription factor.

Abstract Background: Despite evidence of substantial breast cancer risk reduction, few high-risk women adopt chemopreventive medications such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). Women with benign breast disease, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have an increased risk of developing breast cancer and derive a greater benefit from antiestrogens compared to other high-risk women. Reasons for low uptake of chemoprevention include insufficient patient and clinician knowledge about antiestrogens, time constraints during the clinical encounter, and concerns about side effects. To address these barriers, we have developed patient and provider web-based decision support tools to improve informed choice about breast cancer chemoprevention among women with AH or LCIS. Study design: We are conducting a cluster-randomized controlled trial of clinical decision support to improve chemoprevention informed choice among women with AH or LCIS and their treating providers. Twenty-six U.S. sites through the SWOG Cancer Research Network were randomly assigned 1:1 to standard educational materials alone or in combination with the patient-centered decision aid (RealRisks) and provider decision support tool (BNAV). A total of 415 patients and 200 healthcare providers will be recruited from these sites. RealRisks consists of interactive modules to calculate personalized breast cancer risk and elicit preferences on chemoprevention. The modules are available in English and Spanish. BNAV is comprised of self-directed case-based learning modules on breast cancer risk assessment and chemoprevention. Patients complete questionnaires at baseline, 6 and 12 months. Providers complete surveys at baseline and after their enrolled patient’s 6-month clinical encounter. The primary endpoint is chemoprevention informed choice at 6 months, using a measure combining knowledge, attitude, and intention scales. Secondary endpoints include perceived breast cancer risk/worry, chemoprevention knowledge/intention, decision conflict/regret, shared decision-making, and chemoprevention uptake. For patients who begin chemoprevention, adherence and reasons for discontinuation are assessed annually for up to 5 years. Barriers and facilitators to implementing RealRisks and BNAV into clinic workflow will be assessed by conducting patient and provider interviews at baseline and mid-implementation. Eligibility criteria: Eligible patients include women, age 35-74 years, with AH or LCIS, no history of breast cancer, no prior use of SERMs or AIs, no bilateral mastectomies, English or Spanish-speaking, and access to the internet. Eligible providers include breast surgeons, medical oncologists, primary care providers, and physician extenders who see patients with AH or LCIS. Statistical methods: We have 90% power to detect a 15% increase in the frequency of chemoprevention informed choice with a 1-sided 0.025 level test, assuming an intraclass correlation (ICC) of 0.02 to account for clustering, roughly equal accrual at each site, 10% loss to follow-up, and ≤10% event rate in the control arm. Current/target accrual: The trial was activated on 9/1/2020. As of 7/7/2022, all 26 sites have been randomized, 157/200 providers and 184/415 patients have been enrolled. Discussion: Our hybrid effectiveness/implementation study seeks to evaluate the effectiveness of a multi-level intervention in promoting informed decision-making about breast cancer chemoprevention. Study results will provide valuable insights on how the decision support tools are integrated in diverse clinical settings. Citation Format: Katherine D. Crew, Garnet Anderson, Kathryn Arnold, Andrew Stieb, Jacquelyn N. Amenta, Cynthia Law, Ana Sandoval-Leon, Sarah Colonna, Tari King, Debra Mangino, Sandhya Pruthi, Maria Grosse Perdekamp, Christa Braun-Inglis, Stacy Krisher, Lisa Yee, Danielle Bertoni, Samantha Seaward, Kari B. Wisinski, Justin Floyd, Corrine Zarwan, Tarah J. Ballinger, Lindi VanderWalde, Masey M. Ross, Preston Steen, Shelly Lo, Alison Conlin, Kathleen Yost, John Ellerton, Erin Lin, Holly J. Pederson, Sagar Sardesai, Cheryl Jernigan, Dawn Hershman, Marian L. Neuhouser, Banu K. Arun, Rita Kukafka. SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-15-01.