Impaired Whole-Blood Fibrinolysis is a Predictor of Mortality in Intensive Care Patients.

Background Altered fibrinolysis is considered to play a crucial role in the development of coagulopathy in sepsis. However, routine laboratory tests for fibrinolysis are currently very limited, and the impact of fibrinolytic capacity on clinical outcome is poorly investigated. Objectives To assess whole-blood fibrinolysis in patients admitted to the intensive care unit (ICU) and compare fibrinolysis in sepsis patients with nonsepsis patients. Further, to investigate associations between fibrinolytic capacity and 30-day mortality and venous thromboembolism (VTE). Methods This study was designed as a prospective cohort study. Adult ICU patients were included at the Aarhus University Hospital, Denmark. All patients had a blood sample obtained the morning after admission. A modified thromboelastometry (ROTEM®) analysis with tissue plasminogen activator (ROTEM®-tPA) was used to assess fibrinolysis. The primary endpoint was difference in ROTEM®-tPA lysis time between sepsis patients and nonsepsis patients. Results ROTEM®-tPA revealed fibrinolytic impairment in sepsis patients ( n = 30) compared with nonsepsis ICU controls ( n = 129), with longer lysis time (median [interquartile range] 3,600 [3,352-3,600] vs. 3,374 seconds [2,175-3,600], p < 0.01), lower maximum lysis (23 [8-90] vs. 94% [14-100], p = 0.02), and lower fibrinolysis speed (0.41 [0.0-1.4] vs. 1.6 mm/min [0.1-2.7], p = 0.01). In the composite ICU population, 61% (97/159) demonstrated prolonged lysis time indicating impaired fibrinolytic capacity. These patients had higher 30-day mortality (adjusted odds ratio [OR]: 2.26 [0.83-6.69]) and VTE risk (OR: 3.84 [0.87-17.8]) than patients with normal lysis time. Conclusion Sepsis patients showed impaired fibrinolysis measured with ROTEM®-tPA compared with nonsepsis patients and ROTEM®-tPA lysis time was associated with 30-day mortality and VTE in the entire ICU cohort.

The impact of a virtual mind-body program on symptoms of depression and anxiety among international English-speaking adults with neurofibromatosis.

The neurofibromatoses (NFs) are a set of incurable genetic disorders that predispose individuals to nervous system tumors. Although many patients experience anxiety and depression, there is little research on psychosocial interventions in this population. The present study examined the effects of a mind-body intervention on depression and anxiety in adults with NF. This is a secondary analysis of the Relaxation Response Resiliency Program for NF (3RP-NF), an 8-week virtual group intervention that teaches mind-body skills (e.g., relaxation, mindfulness) to improve quality of life. Participants were randomized to 3RP-NF or the Health Enhancement Program for NF (HEP-NF) consisting of health informational sessions and discussion. We evaluated depression (PHQ-9) and anxiety (GAD-7) at posttreatment, 6 months, and 12 months. Both groups improved in depression and anxiety between baseline and posttest, 6 months, and 12 months. The 3RP-NF group showed greater improvements in depression scores from baseline to 6 months compared with HEP-NF and with lower rates of clinically significant depressive symptoms. There were no between-group differences for anxiety. Both interventions reduced distress and anxiety symptoms for individuals with NF. The 3RP-NF group may be better at sustaining these improvements. Given the rare nature of NF, group connection may facilitate reduced distress.

Improving multimodal physical function in adults with heterogeneous chronic pain; Protocol for a multisite feasibility RCT.

BACKGROUND: Chronic pain is associated with substantial impairment in physical function, which has been identified as a top concern among persons with pain. GetActive-Fitbit, a mind-body activity program, is feasible, acceptable, and associated with improvement in physical function among primarily White, sedentary individuals with pain. In preparation for a multisite efficacy trial, we must examine feasibility across multiple sites with diverse patient populations. Here we describe the protocol of a multisite, feasibility RCT comparing GetActive-Fitbit with a time- and attention-matched educational comparison (Healthy Living for Pain). We aim to 1) test multisite fidelity of clinician training; 2) evaluate multisite feasibility benchmarks, including recruitment of chronic pain patients taking <5000 steps/day and racial and ethnic minorities; and 3) optimize fidelity and study protocol in preparation for a future multisite efficacy trial. METHODS: Clinician training fidelity was assessed via roleplays and mock group sessions. Feasibility (i.e., recruitment, acceptability, credibility, adherence, satisfaction), multimodal physical function (e.g., self-report, 6-Minute Walk Test, step-count), and other psychosocial outcomes are assessed at baseline, posttest, and 6 months. Protocol optimization will be assessed using exit interviews and cross-site meetings. RESULTS: The trial is ongoing. Clinician training is complete. 87 participants have been recruited. 54 completed baseline assessments and randomization, 44 are mid-intervention, and 9 have completed the intervention and posttest. CONCLUSIONS: This study addresses the critical need for feasible, acceptable mind-body-activity interventions for chronic pain that follow evidence-based guidelines and improve all aspects of physical function across diverse populations. Results will inform a future fully-powered multisite efficacy trial. CLINICAL TRIAL REGISTRATION: NCT05700383.

Exploring mechanisms of improvement in the Active Brains intervention for older adults with chronic pain and early cognitive decline.

OBJECTIVES: We iteratively developed, optimized, and established the feasibility of a virtual, group-based, mind-body activity program (Active Brains, AB), supported by Fitbit for older adults with chronic pain (CP) and early cognitive decline (ECD). Guided by the principles of the NIH stage model we 1) explore signals of improvement in AB outcomes and hypothesized mechanisms of action and 2) explore relationships between changes in outcomes with changes in mechanisms. METHODS: Participants were N = 15 older adults (age ≥ 60) with CP-ECD from two NIH stage 1 pilot studies of AB. We conducted paired t-tests to explore pre-post improvements, and correlations to investigate associations between changes in outcomes and mechanisms. RESULTS: We observed small to large improvements across co-primary and secondary outcomes (d = 0.24-1.09). We observed small to medium improvements in 4 out of 5 hypothesized mechanisms (d = 0.23-0.47). Overall, improvements in outcomes had moderate to large associations with improvements in hypothesized mechanisms. CONCLUSION: AB was associated with improvements across several co-primary and secondary outcomes, and hypothesized mechanisms. Pain-specific coping and general coping skills are promising treatment targets to address the CP-ECD comorbidity among older adults.

Improving Health for Older Adults With Pain Through Engagement: Protocol for Tailoring and Open Pilot Testing of a Mind-Body Activity Program Delivered Within Shared Medical Visits in an Underserved Community Clinic.

BACKGROUND: Chronic musculoskeletal pain is prevalent and disabling among older adults in underserved communities. Psychosocial pain management is more effective than pharmacological treatment in older adults. However, underserved community clinics often lack psychosocial treatments, in part because of a lack of trained providers. Shared medical appointments, in which patients undergo brief medical evaluation, monitoring, counseling, and group support, are an efficacious and cost-effective method for chronic disease management in underserved clinics, reducing the need for specialized providers. However, shared medical visits are often ineffective for chronic pain, possibly owing to lack of inclusion of skills most relevant for older adults (eg, pacing to increase engagement in daily activities). OBJECTIVE: We have described the protocol for the development and initial pilot effectiveness testing of the GetActive+ mind-body activity intervention for older adults with chronic pain. GetActive+ was adapted from GetActive, an evidence-based intervention that improved pain outcomes among mostly affluent White adults. We aim to establish the initial feasibility, acceptability, fidelity, and effectiveness of GetActive+ when delivered as part of shared medical appointments in a community clinic. METHODS: We conducted qualitative focus groups and individual interviews with providers (n=25) and English-speaking older adults (aged ≥55 y; n=18) with chronic pain to understand the pain experience in this population, perceptions about intervention content, and barriers to and facilitators of intervention participation and implementation in this setting. Qualitative interviews with Spanish-speaking older adults are in progress and will inform a future open pilot of the intervention in Spanish. We are currently conducting an open pilot study with exit interviews in English (n=30 individuals in total). Primary outcomes are feasibility (≥75% of patients who are approached agree to participate), acceptability (≥75% of patients who enrolled complete 8 out of 10 sessions; qualitative), and fidelity (≥75% of session components are delivered as intended). Secondary outcomes include physical function-self-reported, performance based (6-minute walk test), and objective (step count)-and emotional function (depression and anxiety). Other assessments include putative mechanisms (eg, mindfulness and pain catastrophizing). RESULTS: We began enrolling participants for the qualitative phase in November 2022 and the open pilot phase in May 2023. We completed the qualitative phase with providers and English-speaking patients, and the results are being analyzed using a hybrid, inductive-deductive approach. We conducted rapid analysis of these data to develop GetActive+ before the open pilot in English, including increasing readability and clarity of language, reducing the number of skills taught to increase time for individual check-ins and group participation, and increasing experiential exercises for skill uptake. CONCLUSIONS: We provide a blueprint for the refinement of a mind-body activity intervention for older adults with chronic pain in underserved community clinics and for incorporation within shared medical visits. It will inform a future, fully powered, effectiveness-implementation trial of GetActive+ to help address the chronic pain epidemic among older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT05782231; https://clinicaltrials.gov/study/NCT05782231. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52117.

A Live Video Dyadic Resiliency Intervention to Prevent Chronic Emotional Distress Early After Dementia Diagnoses: Protocol for a Dyadic Mixed Methods Study.

BACKGROUND: By 2030, approximately 75 million adults will be living with Alzheimer disease and related dementias (ADRDs). ADRDs produce cognitive, emotional, and behavioral changes for persons living with dementia that undermine independence and produce considerable stressors for persons living with dementia and their spousal care-partners-together called a "dyad." Clinically elevated emotional distress (ie, depression and anxiety symptoms) is common for both dyad members after ADRD diagnosis, which can become chronic and negatively impact relationship functioning, health, quality of life, and collaborative management of progressive symptoms. OBJECTIVE: This study is part of a larger study that aims to develop, adapt, and establish the feasibility of Resilient Together for Alzheimer Disease and Related Dementias (RT-ADRD), a novel dyadic skills-based intervention aimed at preventing chronic emotional distress. This study aims to gather comprehensive information to develop the first iteration of RT-ADRD and inform a subsequent open pilot. Here, we describe the proposed study design and procedures. METHODS: All procedures will be conducted virtually (via phone and Zoom) to minimize participant burden and gather information regarding feasibility and best practices surrounding virtual procedures for older adults. We will recruit dyads (up to n=20) from Mount Sinai Hospital (MSH) clinics within 1 month of ADRD diagnosis. Dyads will be self-referred or referred by their treating neurologists and complete screening to assess emotional distress and capacity to consent to participate in the study. Consenting dyads will then participate in a 60-minute qualitative interview using an interview guide designed to assess common challenges, unmet needs, and support preferences and to gather feedback on the proposed RT-ADRD intervention content and design. Each dyad member will then have the opportunity to participate in an optional individual interview to gather additional feedback. Finally, each dyad member will complete a brief quantitative survey remotely (by phone, tablet, or computer) via a secure platform to assess feasibility of assessment and gather preliminary data to explore associations between proposed mechanisms of change and secondary outcomes. We will conduct preliminary explorations of feasibility markers, including recruitment, screening, live video interviews, quantitative data collection, and mixed methods analyses. RESULTS: This study has been approved by the MSH Institutional Review Board. We anticipate that the study will be completed by late 2023. CONCLUSIONS: We will use results from this study to develop the first live video telehealth dyadic resiliency intervention focused on the prevention of chronic emotional distress in couples shortly after ADRD diagnoses. Our study will allow us to gather comprehensive information from dyads on important factors to address in an early prevention-focused intervention and to explore feasibility of study procedures to inform future open pilot and pilot feasibility randomized control trial investigations of RT-ADRD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45532.

Focus Group Study of Medical Stakeholders to Inform the Development of Resilient Together for Dementia: Protocol for a Postdiagnosis Live Video Dyadic Resiliency Intervention.

BACKGROUND: Alzheimer disease and related dementias (ADRD) are increasingly common conditions that disrupt the lives of persons living with dementia and their spousal care partners. At the time of ADRD diagnoses, many couples experience challenges that produce emotional distress and relationship strain. At present, there are no interventions to address these challenges early after diagnoses to promote positive adjustment. OBJECTIVE: The study protocol described here is part of the first phase of a larger program of research that aims to develop, adapt, and establish the feasibility of Resilient Together for Dementia (RT-ADRD), a novel dyadic skills-based intervention to be delivered over live video early after diagnosis, with the goal of preventing chronic emotional distress. This study will elicit and systematically summarize perspectives of ADRD medical stakeholders to inform the procedures (eg, recruitment and screening methods, eligibility, timing of intervention, and intervention delivery) of the first iteration of RT-ADRD prior to pilot-testing. METHODS: We will recruit interdisciplinary medical stakeholders (eg, neurologists, social workers, neuropsychologists, care coordinators, and speech language pathologists) from academic medical center clinics in the departments treating persons living with dementia such as neurology, psychiatry, and geriatric medicine via flyers and word-of-mouth referrals from clinic directors and members of relevant organizations (eg, dementia care collaboratives and Alzheimer disease research centers). The participants will complete electronic screening and consent procedures. Consenting individuals will then participate in a 30- to 60-minute qualitative virtual focus group, held either via telephone or Zoom, using an interview guide designed to assess provider experiences with postdiagnosis clinical care and to gather feedback on the proposed RT-ADRD protocol. The participants will also have the opportunity to participate in an optional exit interview and web-based survey to gather additional feedback. Qualitative data will be analyzed using a hybrid inductive-deductive approach and the framework method for thematic synthesis. We will conduct approximately 6 focus groups with 4-6 individuals in each group (maximum N=30 individuals; until saturation is reached). RESULTS: Data collection began in November 2022 and will continue through June 2023. We anticipate that the study will be completed by late 2023. CONCLUSIONS: The results from this study will inform the procedures of the first live video RT-ADRD dyadic resiliency intervention focused on the prevention of chronic emotional and relational distress in couples shortly after ADRD diagnoses. Our study will allow us to gather comprehensive information from stakeholders on ways to best deliver our early prevention-focused intervention and gain detailed feedback on study procedures prior to further testing. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45533.

A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus.

Chemoradiotherapy is the primary treatment for patients with squamous cell carcinoma of the anus, but variations in the reported outcomes have restricted between-study comparisons. Treatment-related morbidity is considerable; however, no trial has comprehensively quantified long-term side-effects or quality of life. Therefore, we established the first international health-care professional and patient consensus to develop a core outcome set, using the Core Outcome Measures in Effectiveness Trials method. We used the results from our previous systematic review and combined them in this Review with patient interviews to derive a comprehensive list of outcomes, followed by a two-round Delphi survey completed by 149 participants (55 patients and 94 health-care professionals) from 11 countries. The Delphi results were discussed at a consensus meeting of health-care professionals and patients. Agreement was reached on 19 outcomes across four domains: disease activity, survival, toxicity, and life impact. Implementation of the Core Outcome Research Measures in Anal Cancer (CORMAC) set in future trials will serve as a framework to achieve standardisation, facilitate selection of health-area-specific evaluation tools, reduce redundancy of outcome lists, allow between-study comparisons, and ultimately enhance the relevance of trial findings to health-care professionals, trialists, and patients.

A phase 2 study of SP1049C, doxorubicin in P-glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.

PURPOSE: To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients with metastatic or locally advanced unresectable adenocarcinoma of the esophagus or GEJ who had not previously received systemic chemotherapy and had measurable disease were treated with SP1049C 75 mg/m(2) (doxorubicin equivalents) as a brief intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate in patients who had received a least one course of SP1049C and had undergone tumor assessment, whereas, secondary endpoints included the objective response rate, progression-free survival (PFS), overall survival, and safety in the intent-to-treat (ITT) population. A review of scans was also conducted post-hoc by a blinded panel of radiologists. RESULTS: Twenty-one patients, of which 19 were evaluable for response, were treated with at least one dose of SP1049C. Nine patients had a partial response (PR) and eight patients had either a minor response or stable disease as their best response. The objective response rate was 47% (95% CI: 24.4-71) in the evaluable patient population, whereas the objective response rate was 43% (95% CI: 21.8-65.9) in the ITT population. The post-hoc radiological review confirmed that all nine responders had a PR; seven of the nine had a PR that was confirmed by a subsequent scan, whilst two patients had unconfirmed PRs. The median overall survival and PFS were 10.0 months (95%CI: 4.8-11.2) and 6.6 months (95% CI: 4.5-7.6), respectively. Neutropenia was the principal toxicity of SP1049C. Four patients developed an absolute percentage decrement of at least 15% in their left ventricular ejection fraction, none of which decreased to below 45% nor were symptomatic. CONCLUSION: SP1049C has a notable single-agent activity in patients with adenocarcinoma of the esophagus and GEJ, as well as an acceptable safety profile. These results, in addition to the results of preclinical studies demonstrating superior antitumor activity of SP1049C compared with doxorubicin in a standard formulation, indicate that further evaluations of SP1049C alone or combined with other relevant therapeutics in this disease setting are warranted.