Designing mHealth Apps to Incorporate Evidence-Based Techniques for Prolonging User Engagement.

Maintaining user engagement with mobile health (mHealth) apps can be a challenge. Previously, we developed a conceptual model to optimize patient engagement in mHealth apps by incorporating multiple evidence-based methods, including increasing health literacy, enhancing technical competence, and improving feelings about participation in clinical trials. This viewpoint aims to report on a series of exploratory mini-experiments demonstrating the feasibility of testing our previously published engagement conceptual model. We collected data from 6 participants using an app that showed a series of educational videos and obtained additional data via questionnaires to illustrate and pilot the approach. The videos addressed 3 elements shown to relate to engagement in health care app use: increasing health literacy, enhancing technical competence, and improving positive feelings about participation in clinical trials. We measured changes in participants' knowledge and feelings, collected feedback on the videos and content, made revisions based on this feedback, and conducted participant reassessments. The findings support the feasibility of an iterative approach to creating and refining engagement enhancements in mHealth apps. Systematically identifying the key evidence-based elements intended to be included in an app's design and then systematically testing the implantation of each element separately until a satisfactory level of positive impact is achieved is feasible and should be incorporated into standard app design. While mHealth apps have shown promise, participants are more likely to drop out than to be retained. This viewpoint highlights the potential for mHealth researchers to test and refine mHealth apps using approaches to better engage users.

Correction: Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

[This corrects the article DOI: 10.2196/49100.].

Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

BACKGROUND: Timely collection of patient-reported outcomes (PROs) decreases emergency department visits and hospitalizations and increases survival. However, little is known about the outcome predictivity of unpaid informal caregivers' reporting using similar clinical outcome assessments. OBJECTIVE: The aim of this study is to assess whether caregivers and adults with cancer adhered to a planned schedule for electronically collecting patient-reported outcomes (PROs) and if PROs were associated with future clinical events. METHODS: We developed 2 iPhone apps to collect PROs, one for patients with cancer and another for caregivers. We enrolled 52 patient-caregiver dyads from Kaiser Permanente Northern California in a nonrandomized study. Participants used the apps independently for 4 weeks. Specific clinical events were obtained from the patients' electronic health records up to 6 months following the study. We used logistic and quasi-Poisson regression analyses to test associations between PROs and clinical events. RESULTS: Participants completed 97% (251/260) of the planned Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) surveys and 98% (254/260) of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys. PRO-CTCAE surveys completed by caregivers were associated with patients' hospitalizations or emergency department visits, grade 3-4 treatment-related adverse events, dose reductions (P<.05), and hospice referrals (P=.03). PROMIS surveys completed by caregivers were associated with hospice referrals (P=.02). PRO-CTCAE surveys completed by patients were not associated with any clinical events, but their baseline PROMIS surveys were associated with mortality (P=.03), while their antecedent or final PROMIS surveys were associated with all clinical events examined except for total days of treatment breaks. CONCLUSIONS: In this study, caregivers and patients completed PROs using smartphone apps as requested. The association of caregiver PRO-CTCAE surveys with patient clinical events suggests that this is a feasible approach to reducing patient burden in clinical trial data collection and may help provide early information about increasing symptom severity.

What Works Best to Engage Participants in Mobile App Interventions and e-Health: A Scoping Review.

Background: Despite the growing popularity of mobile app interventions, specific engagement components of mobile apps have not been well studied. Methods: The objectives of this scoping review are to determine which components of mobile health intervention apps encouraged or hindered engagement, and examine how studies measured engagement. Results: A PubMed search on March 5, 2020 yielded 239 articles that featured the terms engagement, mobile app/mobile health, and adult. After applying exclusion criteria, only 54 studies were included in the final analysis. Discussion: Common app components associated with increased engagement included: personalized content/feedback, data visualization, reminders/push notifications, educational information/material, logging/self-monitoring functions, and goal-setting features. On the other hand, social media integration, social forums, poor app navigation, and technical difficulties appeared to contribute to lower engagement rates or decreased usage. Notably, the review revealed a great variability in how engagement with mobile health apps is measured due to lack of established processes. Conclusion: There is a critical need for controlled studies to provide guidelines and standards to help facilitate engagement and its measurement in research and clinical trial work using mobile health intervention apps.

Development of a Mobile Health App (TOGETHERCare) to Reduce Cancer Care Partner Burden: Product Design Study.

BACKGROUND: Approximately 6.1 million adults in the United States serve as care partners for cancer survivors. Studies have demonstrated that engaging cancer survivors and their care partners through technology-enabled structured symptom collection has several benefits. Given the high utilization of mobile technologies, even among underserved populations and in low resource areas, mobile apps may provide a meaningful access point for all stakeholders for symptom management. OBJECTIVE: We aimed to develop a mobile app incorporating user preferences to enable cancer survivors' care partners to monitor the survivors' health and to provide care partner resources. METHODS: An iterative information gathering process was conducted that included (1) discussions with 138 stakeholders to identify challenges and gaps in survivor home care; (2) semistructured interviews with clinicians (n=3), cancer survivors (n=3), and care partners (n=3) to identify specific needs; and (3) a 28-day feasibility field test with seven care partners. RESULTS: Health professionals noted the importance of identifying early symptoms of adverse events. Survivors requested modules on medication, diet, self-care, reminders, and a version in Spanish. Care partners preferred to focus primarily on the patient's health and not their own. The app was developed incorporating quality-of-life surveys and symptom reporting, as well as resources on home survivor care. Early user testing demonstrated ease of use and app feasibility. CONCLUSIONS: TOGETHERCare, a novel mobile app, was developed with user input to track the care partner's health and report on survivor symptoms during home care. The following two clinical benefits emerged: (1) reduced anxiety among care partners who use the app and (2) the potential for identifying survivor symptoms noted by the care partner, which might prevent adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT04018677; https://clinicaltrials.gov/ct2/show/NCT04018677.

Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis.

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1.

PURPOSE: Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immunosuppressive phenotype; however, mechanisms have been elusive. EXPERIMENTAL DESIGN: Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity. RESULTS: CD44(+) cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44(-) cells when cultured with autologous CD8(+) tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44(+) cells compared with CD44(-) cells and was associated with constitutive phosphorylation of STAT3 on CD44(+) cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44(+) cells. IFNγ treatment preferentially induced even further PD-L1 expression on CD44(+) cells and was associated with enhanced IFNγ receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44(+) cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44(+) and CD44(-) cells are biologically and clinically relevant. CONCLUSIONS: Our findings provide a mechanism by which long-lived CD44(+) tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN. Clin Cancer Res; 22(14); 3571-81. ©2016 AACR.

Individuality and variation of personal regulomes in primary human T cells.

Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

Drug-Induced Thrombocytopenia following a Transvaginal Oocyte Retrieval for In Vitro Fertilization.

Drug-induced immune thrombocytopenia has been associated with hundreds of medications and can lead to devastating consequences for the patient. We present a case of a healthy 33-year-old female undergoing in vitro fertilization who developed a severe drug-induced thrombocytopenia, petechiae, and a large hemoperitoneum after receiving Cefazolin antibiotic prophylaxis for a transvaginal oocyte retrieval. The patient was admitted to the intensive care unit for resuscitation with blood products. The presence of drug-dependent platelet antibodies to Cefazolin was confirmed serologically.

Intravascular crystal deposition: an early clue to the diagnosis of type 1 cryoglobulinemic vasculitis.

Cutaneous small vessel vasculitis (CSVV) is a nonspecific finding with an extensive differential diagnosis. It is critically important to distinguish skin-limited presentations of CSVV from severe life-threatening systemic vasculitides presenting with CSVV as an initial manifestation. It can be challenging to determine which patients presenting with CSVV are at risk for systemic disease. Standard histopathologic evaluation, direct immunofluorescence, and serologic evaluation is typically required to exclude a systemic vasculitis. Type 1 cryoglobulinemia may rarely present with CSVV. Herein, we report a case of type 1 cryoglobulinemia in the setting of occult multiple myeloma. CSVV with prominent intravascular crystal formation was noted. The presence of intravascular crystals in the setting of CSVV may represent an important early clue to the diagnosis of type 1 cryoglobulinemic vasculitis.

A pilot study on providing ophthalmic training to medical students while initiating a sustainable eye care effort for the underserved.

IMPORTANCE: We present a method to reintroduce ophthalmic training into the medical school curriculum. OBJECTIVES: To evaluate knowledge and skills acquired when participating in a service project, the Community Vision Project, and to develop a quantitative method for testing skills with the direct ophthalmoscope in patients. DESIGN: Second-year medical students participated in the study. After 1 month, their knowledge was compared with that of peers and graduates (internal medicine residents). Also at 1 month, their direct ophthalmoscope skills were compared with those of upperclassmen who had completed all core clerkships. One year later, after the participants had completed their core clerkships, long-term ophthalmoscope skills retention was tested, and their performance was compared with that of their classmates. SETTING AND PARTICIPANTS: Training occurred in mobile eye clinics. Knowledge and skills assessments were performed in the hospital eye clinic among students and residents at The University of New Mexico School of Medicine. Patients were recruited from the hospital eye clinic. Participants attended a 3-hour training session held by an attending physician in the hospital eye clinic and took part in at least 1 mobile eye clinic. MAIN OUTCOMES AND MEASURES: A knowledge assessment quiz was administered to participants (n = 12), their classmates (n = 18), and internal medicine residents (n = 33). Skills assessment with the direct ophthalmoscope was performed at 1 month and at 1 year in 5 participants and 5 nonparticipants. Tonometer skills were assessed by comparing participants' readings with those of an ophthalmologist's obtained in patients at the mobile eye clinics. RESULTS Participants' median knowledge assessment scores were 48% higher than those of their classmates and 37% higher than those of internal medicine residents (P < .001 for both). Short-term (1 month) direct ophthalmoscopy median scores were 60% (quartile 1 to quartile 3 range, 40%-80%) for participants and 40% (quartile 1 to quartile 3 range, 20%-60%) for nonparticipating upperclassmen (P = .24). Long-term direct ophthalmoscopy median scores were 100% (quartile 1 to quartile 3 range, 75%-100%) for participants and 0% (quartile 1 to quartile 3 range, 0%-25%) for nonparticipating classmates (P = .11). Participants' tonometer readings were similar to those of the ophthalmologist's; their median reading was 2 mm Hg (quartile 1 to quartile 3 range, 0-4 mm Hg) higher than that of the ophthalmologist's (P = .05, sign test). CONCLUSIONS AND RELEVANCE: Service-based learning offered an efficient model for incorporating ophthalmic training into the medical school curriculum. A viable tool for quantitatively testing ophthalmoscope skills is presented.

Dendrimers as high relaxivity MR contrast agents.

Dendrimers are versatile macromolecules with tremendous potential as magnetic resonance imaging (MRI) contrast agents. Dendrimer-based agents provide distinct advantages over low-molecular-weight gadolinium chelates, including enhanced r1 relaxivity due to slow rotational dynamics, tunable pharmacokinetics that can be adapted for blood pool, liver, kidney, and lymphatic imaging, the ability to be a drug carrier, and flexibility for labeling due to their inherent multivalency. Clinical applications are increasingly being developed, particularly in lymphatic imaging. Herein we present a broad overview of dendrimer-based MRI contrast agents with attention to the unique chemistry and physical properties as well as emerging clinical applications.

Polychromatic in vivo imaging of multiple targets using visible and near infrared light.

Conventional diagnostic imaging methods such as X-ray CT, MRI, and nuclear medicine are inherently monochromatic meaning that they can depict only one molecular target at a time. Optical imaging has the unique ability to be polychromatic and therefore multi-color imaging employing targeted agents conjugated to fluorophores of varying wavelength enables multiple simultaneous readouts thus providing greater multiplexed information. Numerous successful multicolor imaging techniques have recently been reported using optical imaging in in vivo animal disease models, thus adding to a growing body of research supporting the clinical viability and applicability of these technologies. Herein, we review multicolor optical imaging from the basic chemistry and physics perspective and then extend this to biological and medical applications.

Nerve involvement in granuloma annulare.

BACKGROUND: Nerve involvement developed in a patient with granuloma annulare, as evidenced by a perineural infiltrate of histiocytes in the dermis. The histopathologic pattern was suggestive of leprosy. No mycobacteria were observed, and neurologic testing was normal. OBJECTIVE: To determine whether inflammation of the nerves or perineural tissue is common in granuloma annulare, we studied the cutaneous nerves in skin biopsy specimens from 14 patients with granuloma annulare. METHODS: Sections were stained with hematoxylin-eosin to highlight inflammatory cells and with S-100 to identify cutaneous nerves. RESULTS: No inflammation around nerves was found in 12 specimens, abutting granulomatous inflammation was found in 1 specimen, and enveloping granulomatous inflammation was found in 1 specimen. No nerves were infiltrated by inflammatory cells. CONCLUSION: Perineural granulomatous inflammation resembling the perineural infiltrate of leprosy appears to be an uncommon characteristic of granuloma annulare. Clinical correlation and acid-fast stains can assist in establishing the correct diagnosis.

Rational chemical design of the next generation of molecular imaging probes based on physics and biology: mixing modalities, colors and signals.

In recent years, numerous in vivo molecular imaging probes have been developed. As a consequence, much has been published on the design and synthesis of molecular imaging probes focusing on each modality, each type of material, or each target disease. More recently, second generation molecular imaging probes with unique, multi-functional, or multiplexed characteristics have been designed. This critical review focuses on (i) molecular imaging using combinations of modalities and signals that employ the full range of the electromagnetic spectra, (ii) optimized chemical design of molecular imaging probes for in vivo kinetics based on biology and physiology across a range of physical sizes, (iii) practical examples of second generation molecular imaging probes designed to extract complementary data from targets using multiple modalities, color, and comprehensive signals (277 references).

Biologically optimized nanosized molecules and particles: more than just size.

The expanded biological and medical applications of nanomaterials place a premium on better understanding of the chemical and physical determinants of in vivo particles. Nanotechnology allows us to design a vast array of molecules with distinct chemical and biological characteristics, each with a specific size, charge, hydrophilicity, shape, and flexibility. To date, much research has focused on the role of particle size as a determinant of biodistribution and clearance. Additionally, much of what we know about the relationship between nanoparticle traits and pharmacokinetics has involved research limited to the gross average hydrodynamic size. Yet, other features such as particle shape and flexibility affect in vivo behavior and become increasingly important for designing and synthesizing nanosized molecules. Herein, we discuss determinants of in vivo behavior of nanosized molecules used as imaging agents with a focus on dendrimer-based contrast agents. We aim to discuss often overlooked or, yet to be considered, factors that affect in vivo behavior of synthetic nanosized molecules, as well as aim to highlight important gaps in current understanding.

Near infrared fluorescence-guided real-time endoscopic detection of peritoneal ovarian cancer nodules using intravenously injected indocyanine green.

Near infrared fluorescence-guidance can be used for the detection of small cancer metastases and can aid in the endoscopic management of cancer. Indocyanine green (ICG) is a Food and Drug Administration (FDA)-approved fluorescence agent. Through non-specific interactions with serum proteins, ICG achieves enhanced permeability and retention (EPR) effects. Yet, ICG demonstrates rapid clearance from the circulation. Therefore, ICG may be an ideal contrast agent for real-time fluorescence imaging of tumors. To evaluate the usefulness of real-time dual fluorescence and white light endoscopic optical imaging to detect tumor implants using the contrast agent ICG, fluorescence-guided laparoscopic procedures were performed in mouse models of peritoneally disseminated ovarian cancers. Animals were administered intravenous ICG or a control contrast agent, IR800-conjugated to albumin. The ability to detect small ovarian cancer implants was then compared. Using the dual view microendoscope, ICG clearly enabled visualization of peritoneal ovarian cancer metastatic nodules derived from SHIN3 and OVCAR5 cells at 6 and 24 hr after injection with significantly higher tumor-to-background ratio than the control agent, IR800-albumin (p < 0.001). In conclusion, ICG has the desirable properties of having both EPR effects and rapid clearance for the real-time endoscopic detection of tiny ovarian cancer peritoneal implants compared to a control macromolecular agent with theoretically better EPR effects but longer circulatory retention. Given that ICG is already FDA-approved and has a long track record of human use, this method could be easily translated to the clinic as a robust tool for fluorescence-guided endoscopic procedures for the management and treatment of cancer.