Association Among Chronic Obstructive Pulmonary Disease Severity, Exacerbation Risk, and Anxiety and Depression Symptoms in the SPIROMICS Cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive lung disease that often manifests with psychiatric symptoms. Despite this, patients with COPD are not routinely screened for anxiety and depression, which substantially contribute to COPD-related morbidity. OBJECTIVE: To determine the relationship among COPD symptom severity, exacerbation risk, and clinically significant anxiety and depression symptoms in ever smokers with COPD. METHODS: We used baseline data from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort to examine ever smokers with COPD across Global Initiative for Obstructive Lung Disease (GOLD) disease severity groups. Multivariable logistic regression models were used to calculate odds ratios for clinically significant anxiety and depression for each GOLD group, which was compared to the control group of ever smokers without COPD. Odds ratios were adjusted for subject demographics, medical comorbidities, and substance use covariates, and comparisons were completed using 2-tailed tests. RESULTS: Of the 2664 subjects studied, 784 (29.4%) had clinically significant anxiety, and 497 (18.7%) had clinically significant depression. In the multivariable analysis, high pulmonary symptom groups, groups B and D, had increased adjusted odds of clinically significant anxiety (group B: adjusted odds ratios [AOR] 1.28, P = 0.03; group D: AOR 1.95, P < 0.0001) and depression (group B: AOR 2.09, P < 0.0001; group D: AOR 3.04, P < 0.0001). GOLD group D, the group with high pulmonary symptoms and high COPD exacerbation risk, had the greatest risk of both anxiety and depression among the GOLD groups. CONCLUSIONS: High COPD symptom severity, even in the absence of elevated COPD exacerbation risk, is associated with clinically significant anxiety and depression. Our separate analyses of anxiety and depression symptoms in a large, multisite, national cohort are unique within the literature and have important treatment implications for COPD patients. Our findings also highlight the utility of screening patients with high COPD symptom severity for anxiety and depression.

Infectious viral shedding of SARS-CoV-2 Delta following vaccination: A longitudinal cohort study.

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P = 0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.

Non-convulsive Status Epilepticus in a Patient With Schizoaffective and Seizure Disorder on Clozapine and Electroconvulsive Therapy: A Case Report.

There is limited literature on electroconvulsive therapy (ECT) in patients with a severe schizophrenia spectrum illness and concomitant seizure disorder. In addition, it is unclear whether it is safe to perform ECT in a patient with these comorbidities and a history of status epilepticus. This is the case of a 48-year-old patient with a history of schizoaffective disorder, bipolar type, refractory psychosis on clozapine and ECT, and seizure disorder on carbamazepine. She presented to the emergency department with suspected post-ECT delirium four days after her last ECT treatment, was found to be in non-convulsive status epilepticus, and was admitted to the neuroscience intensive care unit. Coma induction was required for seizure control. As she stabilized, her psychosis worsened, and she required psychiatric hospitalization. Multiple factors may have contributed to the development of status epilepticus in this patient. She was on clozapine, which has a time- and dose-dependent risk of seizure that prescribers should be wary of. She had also been prescribed the antiepileptic drug carbamazepine, which induces clozapine and itself, decreasing their effectiveness. Upon the patient's discharge, ECT was suspended indefinitely due to concern that it may have led to status epilepticus. However, case reports suggest that intractable seizures following ECT are rare. We found no reports of status epilepticus occurring more than 60 minutes after the completion of ECT. If the benefits of ECT are significant, then it should remain a treatment option for the patient.

Persistence, Magnitude, and Patterns of Postacute Symptoms and Quality of Life Following Onset of SARS-CoV-2 Infection: Cohort Description and Approaches for Measurement.

BACKGROUND: There is mounting evidence for the presence of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), but there is limited information on the spectrum, magnitude, duration, and patterns of these sequelae as well as their influence on quality of life. METHODS: We assembled a cohort of adults with a documented history of SARS-CoV-2 RNA positivity at ≥2 weeks past onset of coronavirus disease 2019 (COVID-19) symptoms or, if asymptomatic, first positive test. At 4-month intervals, we queried physical and mental health symptoms and quality of life. RESULTS: Of the first 179 participants enrolled, 10 were asymptomatic during the acute phase of SARS-CoV-2 infection, 125 were symptomatic but not hospitalized, and 44 were symptomatic and hospitalized. During the postacute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping, and anosmia/dysgeusia were most common through 8 months of observation. Symptoms were typically at least somewhat bothersome and sometimes exhibited a waxing-and-waning course. Some participants experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with performance of usual activities. The median visual analogue scale rating of general health was lower at 4 and 8 months compared with pre-COVID-19. Two clusters of symptom domains were identified. CONCLUSIONS: Many participants report bothersome symptoms following onset of COVID-19 with variable patterns of persistence and impact on quality of life. The substantial variability suggests the existence of multiple subphenotypes of PASC. A rigorous approach to the prospective measurement of symptoms and functional manifestations sets the stage for the next phase of research focusing on the pathophysiologic causes of the various subgroups of PASC.

Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome.

The major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the translation of Tfeb, a key executer of the autophagy response. This autophagy survival response is triggered by mitochondrial proteotoxic stress, which allows cancer cell survival. Our screen also reveals a functional interaction between eIF4E and a single anti-apoptotic factor, Bcl-xL, in tumor growth. Furthermore, we show that eIF4E and the exon-junction complex (EJC), which is involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we uncover several cancer-specific vulnerabilities that provide further resolution of the cancer translatome.

Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), attention has turned to characterizing post-acute sequelae of SARS-CoV-2 infection (PASC). METHODS: From April 21 to December 31, 2020, we assembled a cohort of consecutive volunteers who a) had documented history of SARS-CoV-2 RNA-positivity; b) were ≥ 2 weeks past onset of COVID-19 symptoms or, if asymptomatic, first test for SARS-CoV-2; and c) were able to travel to our site in San Francisco. Participants learned about the study by being identified on medical center-based registries and being notified or by responding to advertisements. At 4-month intervals, we asked participants about physical symptoms that were new or worse compared to the period prior to COVID-19, mental health symptoms and quality of life. We described 4 time periods: 1) acute illness (0-3 weeks), 2) early recovery (3-10 weeks), 3) late recovery 1 (12-20 weeks), and 4) late recovery 2 (28-36 weeks). Blood and oral specimens were collected at each visit. RESULTS: We have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Some experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with ambulation and performance of usual activities. The median visual analogue scale value rating of general health was lower at 4 and 8 months (80, interquartile range [IQR]: 70-90; and 80, IQR 75-90) compared to prior to COVID-19 (85; IQR 75-90). Biospecimens were collected at nearly 600 participant-visits. CONCLUSION: Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

Recommendations for the design, implementation and evaluation of social support in online communities, networks, and groups.

A new model of health care is emerging in which individuals can take charge of their health by connecting to online communities and social networks for personalized support and collective knowledge. Web 2.0 technologies expand the traditional notion of online support groups into a broad and evolving range of informational, emotional, as well as community-based concepts of support. In order to apply these technologies to patient-centered care, it is necessary to incorporate more inclusive conceptual frameworks of social support and community-based research methodologies. This paper introduces a conceptualization of online social support, reviews current challenges in online support research, and outlines six recommendations for the design, evaluation, and implementation of social support in online communities, networks, and groups. The six recommendations are illustrated by CanConnect, an online community for cancer survivors in middle Tennessee. These recommendations address the interdependencies between online and real-world support and emphasize an inclusive framework of interpersonal and community-based support. The applications of these six recommendations are illustrated through a discussion of online support for cancer survivors.

Building a shared vision for an online cancer survivorship community.

In order to achieve comprehensive, closed-loop care for cancer survivors, new strategies are needed to bring together patients, providers, and support services in local communities. To address this challenge, an online community for cancer survivorship was envisioned and designed collaboratively by cancer survivors, family members, community professionals, and informatics researchers in middle Tennessee. The vision developed by the community members serves as a foundation for medical informatics systems to build capacity in local communities to improve cancer care and social support. Using ecological systems theory and social capital as theoretical frameworks, key themes are identified for the future of communication and collaboration in cancer survivorship.

Synthesizing community wisdom: A model for sharing cancer-related resources through social networking and collaborative partnerships.

Despite the availability of community-based support services, cancer patients and survivors are not aware of many of these resources. Without access to community programs, cancer survivors are at risk for lower quality of care and lower quality of life. At the same time, non-profit community organizations lack access to advanced consumer informatics applications to effectively promote awareness of their services. In addition to the current models of print and online resource guides, new community-driven informatics approaches are needed to achieve the goal of comprehensive care for cancer survivors. We present the formulation of a novel model for synthesizing a local communitys collective wisdom of cancer-related resources through a combination of online social networking technologies and real-world collaborative partnerships. This approach can improve awareness of essential, but underutilized community resources.

Crossing the implementation chasm: a proposal for bold action.

As health care organizations dramatically increase investment in information technology (IT) and the scope of their IT projects, implementation failures become critical events. Implementation failures cause stress on clinical units, increase risk to patients, and result in massive costs that are often not recoverable. At an estimated 28% success rate, the current level of investment defies management logic. This paper asserts that there are "chasms" in IT implementations that represent risky stages in the process. Contributors to the chasms are classified into four categories: design, management, organization, and assessment. The American College of Medical Informatics symposium participants recommend bold action to better understand problems and challenges in implementation and to improve the ability of organizations to bridge these implementation chasms. The bold action includes the creation of a Team Science for Implementation strategy that allows for participation from multiple institutions to address the long standing and costly implementation issues. The outcomes of this endeavor will include a new focus on interdisciplinary research and an inter-organizational knowledge base of strategies and methods to optimize implementations and subsequent achievement of organizational objectives.

Blogs, wikis, and discussion forums: attributes and implications for clinical information systems.

Informaticians increasingly view clinical information systems as asynchronous communication systems instead of data processing tools. Outside of health care, popular web technologies like blogs, wikis, and discussion forums have proven to be platforms for effective asynchronous communication. These popular technologies have implications for improving the coordination of clinical care and social support. In order to appropriately evaluate these webbased tools for use in clinical information systems, it will be essential for the informatics community to formally identify the distinguishing attributes of these communication methodologies. The authors propose seven interpersonal and informational attributes to compare and contrast the purposes of blogs, wikis, and discussion forums. This attribute-based approach to analyzing emerging web technologies will lead to a better understanding of the design choices involved in web-based information systems. Two case studies demonstrate how informatics researchers and developers can consider these attributes in the design and evaluation of clinical information systems.

Challenges of social networking technologies for cancer care and social support.

Online communities and web-based messaging tools are valuable tools for cancer care and social support. Developers of these systems should be prepared to address the challenges of including social networking and emerging web technologies in clinical and consumer informatics systems. Experiences and challenges from a pilot test of a web-based messaging and social networking system for cancer patients will be discussed, and recommendations are offered for system design and adoption.

Interface design for patient-caregiver integrated network.

Communication surrounding cancer treatment involves clinicians, patients, families, friends and others affected by the illness. The aim of this work is to create an informatics system that can support the communication needs of cancer patients and their formal and informal caregivers. Based on interviews with patients and family/friend caregivers, a prototype web-based communication system was created with an emphasis on the interpersonal relationships between patients, families, and clinicians.

A framework for clinical communication supporting healthcare delivery.

Interpersonal communications related to healthcare delivery, called clinical communications, take up a considerable amount of time. Nonetheless, there exist few tools in electronic health record systems that support clinical communications. We describe a framework for clinical communications and describe our experiences implementing tools to manage and document them within an electronic health record system. Categories of clinical communications include communications between patients and healthcare providers, among healthcare providers on a single clinical team, between healthcare providers in different clinical teams and different institutions, and between healthcare providers and individuals who can provide additional educational or evidence based materials to support care delivery.

Online communication and support for cancer patients: a relationship-centric design framework.

Dealing with a cancer diagnosis and cancer treatment involves communication among clinicians, patients, families, friends and others affected by the illness. The hypothesis of this research is that an informatics system can effectively support the communication needs of cancer patients and their informal caregivers. Two design frameworks for online cancer communication are defined and compared. One is centered primarily on the users' interpersonal relationships, and the other is centered on the clinical data and cancer information. Five types of clinical and supportive relationships were identified and supported by in-depth interviews with cancer patients and their informal caregivers. Focusing the design of an online cancer communication system around the interpersonal relationships of patients and families may be an important step towards designing more effective paradigms for online cancer care and support.